Parkinson's disease and mitochondrial gene variations: A review

JNS-13367; No of Pages 9 Journal of the Neurological Sciences xxx (2014) xxx–xxx

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Review article

Parkinson's disease and mitochondrial gene variations: A review Sasan Andalib a,⁎, Manouchehr Seyedi Vafaee b, Albert Gjedde b a b

Neurosciences Research Center, Imam Reza Hospital, Tabriz University of Medical Sciences, Tabriz, Iran Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

a r t i c l e

i n f o

Article history: Received 21 December 2013 Received in revised form 29 July 2014 Accepted 31 July 2014 Available online xxxx Keywords: Parkinson's disease Mitochondrial DNA variations Mitochondrial dysfunction Mitochondrial DNA nucleotide position Genetic susceptibility Central nervous system

a b s t r a c t Parkinson's disease (PD) is a common disorder of the central nervous system in the elderly. The pathogenesis of PD is a complex process, with genetics as an important contributing factor. This factor may stem from mitochondrial gene variations and mutations as well as from nuclear gene variations and mutations. More recently, a particular role of mitochondrial dysfunction has been suggested, arising from mitochondrial DNA variations or acquired mutations in PD pathogenesis. The present review summarizes and weighs the evidence in support of mitochondrial DNA (mtDNA) variations as important contributors to the development and course of PD. © 2014 Elsevier B.V. All rights reserved.

Contents 1.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Mitochondrial DNA (mtDNA) and oxidative phosphorylation (OXPHOS) . . . 1.2. Nuclear gene variations and mutations in PD . . . . . . . . . . . . . . . 1.3. Nuclear gene variations and mutations with mitochondrial dysfunction in PD 1.4. Mitochondrial DNA variations and mutations in PD . . . . . . . . . . . . 1.5. Mitochondrial DNA deletions in PD . . . . . . . . . . . . . . . . . . . 1.6. Mitochondrial DNA variations common to both AD and PD . . . . . . . . 1.7. LHON-related mtDNA variations and mutations in PD . . . . . . . . . . . 2. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Parkinson's disease (PD) is the second most common degenerative disorder of the central nervous system (CNS) surpassed only by Alzheimer's disease (AD) [1]. The incidence of PD is 8–18 per 100.000 person-years, and the prevalence is roughly 0.3% of the entire population [2]. PD affects more than 1% of people older than 60 of age and as many as 4% of those older than 80 years [2]. The etiology of PD has long been thought to include both genetics and environment [3]. As yet, there is no direct evidence to support either etiology as a causative factor. Attention to the genetic basis of PD recently resulted in ⁎ Corresponding author. Tel./fax: +98 4133340730. E-mail address: [email protected] (S. Andalib).

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different genes having been identified as contributory to PD. A single mutation may produce a heterogeneous PD phenotype [4]. It is postulated that PD not only can stem from nuclear gene variations and mutations, but that it also can result from mitochondrial gene variations and mutations. This paper reviews the evidence that mitochondrial DNA variations contribute to PD. As the most apparent symptom, patients afflicted with PD present with tremor [5]. This typically is evident at rest, when the limb is relaxed, and disappears with voluntary movement and sleep [5]. Bradykinesia, slowness of movement, is another manifestation of PD [6], which appears as the most disabling symptom in the early stages of the disease [7], as well as rigidity, which is resistance to limb movements [5]. Postural instability [8], leading to impaired balance, festinating gait [9], and facial motion [5] are less common characteristics of the disease. In

http://dx.doi.org/10.1016/j.jns.2014.07.067 0022-510X/© 2014 Elsevier B.V. All rights reserved.

Please cite this article as: Andalib S, et al, Parkinson's disease and mitochondrial gene variations: A review, J Neurol Sci (2014), http://dx.doi.org/ 10.1016/j.jns.2014.07.067

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S. Andalib et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx

addition to the limitation of movement, patients afflicted with PD may suffer from mild to severe neuropsychiatric disturbances, including disorders of speech and swallowing [10], mood [11], sleep [12], cognition [13], behavior and thought [5]. The motor symptoms of PD stem from an imbalance of two neurotransmitters, dopamine and acetylcholine [14] due to the loss of dopaminergic cells in the ventral part of the pars compacta of the substantia nigra (SN) [15]. The cause of cell loss in PD is unresolved, but several mechanisms by which neurons can degenerate have been investigated [16] including the intraneuronal accumulation of the alpha-synuclein (SNCA) protein [17]. The aggregation of this protein creates inclusions in the neurons known as Lewy bodies [15,18]. Proteosomal and lysosomal system dysfunction and reduced mitochondrial activity are also signs of the disease [16]. PD is usually diagnosed by medical history and neurological examination [5]. Neuroimaging sometimes is used to identify PD, but no single laboratory test yields an accurate diagnosis of the disease. PD progresses through the five stages defined by the Hoehn and Yahr scale [19] and as rated by the Movement Disorder Society's Unified Parkinson's Disease Rating Scale (MDS-UPDRS) used in PD diagnosis [20]. PD is an incurable disease, but Levodopa (L-DOPA) therapy raises the life expectancy [21]. L-DOPA is converted into dopamine in the dopaminergic and other neurons containing enzyme Aromatic Amino Acid Decarboxylase (AAAD), also known as DOPA decarboxylase (DDC). Drugs that improve the symptoms generally raise dopamine, block dopamine breakdown, or mimic dopamine action. Of these, L-DOPA is administered with a peripheral DDC inhibitor to elevate dopamine in the brain of PD patients [22]. Dopamine agonists mimic dopamine action [23], and MAO-B inhibitors block dopamine breakdown [24]. Among drugs that exert an anti-Parkinsonian effect by raising dopamine, modafinil also lowers oxidative stress [25]. Active treatment can modulate neuronal activity and the hemodynamic response in basal ganglia of patients with PD [26] and motor symptoms of PD can be improved by bilateral high-frequency electrical stimulation of the subthalamic nucleus (STN) [27]. PD is known as idiopathic Parkinson disease when no known cause is evident. The pathogenesis of PD is a complex process; but recently, it has been attributed also to genetic factors [3]. Approximately 15% of patients with PD have a first-degree relative suffering from PD [7] and susceptibility to PD increases in first-degree relatives of both sporadic and familial cases [28] with increased risk of PD in parents and siblings of patients [29]. Evidently, PD is transmitted in some families as an autosomal dominant [4], or autosomal recessive [30] disorder, and 5% of patients with PD has a mutation of one of several specific nuclear genes [31] including α-synuclein (SNCA), PARKIN, PTEN-induced putative kinase 1 (Pink1), DJ1 or leucine-rich repeat kinase 2 gene (LRRK2), and HTR2A [32,33]. Mutations in the LRRK2 [34] and SNCA [35]result in autosomal dominant PD, while the proteins implicated in autosomal recessive PD include PARKIN [36], PINK1 [37], DJ-1 [38] and ATP13A2 [39]. 1.1. Mitochondrial DNA (mtDNA) and oxidative phosphorylation (OXPHOS) The mitochondria are cytoplasmic organelles involved in OXPHOS and adenosine triphosphate (ATP) production. MtDNA includes multiple copies of a circular structure of 16,569 base pairs [40] that are active in the synthesis of mitochondrial ribonucleic acids (RNAs) and proteins. The mitochondrial genome, depicted in Fig. 1, contains 37 intronless genes, which encode 13 subunits of the electron-transfer chain, 2 ribosomal RNA, and 22 transfer RNA [41] and is inherited exclusively from the mother [42]. The respiratory chain in the mitochondria is composed of 5 protein complexes, and of the 46 subunits of complex I, 7 proteins (ND1, ND2, ND3, ND4, ND4l, ND5, and ND6) are encoded by mtDNA, while all 4 subunits of complex II are produced by nuclear genes. Cytochrome b is the only protein of the 3 subunits of complex III that is expressed by mtDNA. Of the 13 subunits of complex IV, three proteins (COX I, COX II and COX III) are encoded by mtDNA and of the 16 subunits of complex V, two proteins (A6 and A8) are encoded by mtDNA.

Fig. 1. Human mitochondrial genes. MtDNA (mitochondrial DNA); rRNA (ribosomal RNA); Nd (NADH Dehydrogenase); COX (cytochrome oxidase); CYTb (cytochrome b).

Of these genes, those of complex I genes are said to be the most vulnerable parts of mtDNA [43]. The mitochondria function as cellular energy factories [44]. Their dysfunction leads to failure of ATP synthesis and impaired calcium buffering [45] and they are the most important intracellular source of reactive oxygen species (ROS) [46]. Superoxide radical and its reactive metabolites, that is, ROS, are formed by approximately 2% of oxygen in and around the mitochondria [47]. On one hand, increased ROS generation damages cell membranes and raises the rate of mtDNA mutations, on the other, mtDNA mutations in turn lead to energy failure, oxidative damage, ROS generation, and aging [48]. The mutations cause mitochondrial dysfunction, and the impairment of mitochondrial respiration and OXPHOS further augments the oxidative stress, resulting in mtDNA rearrangements and deletions [49]. Compared to other organs, the brain is susceptible to oxidative damage because of its high rate of peroxidation of unsaturated fatty acids, the high levels of oxygen consumption, and the relative scarcity of antioxidant enzymes [50]. The mitochondria are critical regulators of cell death, a key feature of neurodegeneration [51], and ROS damage is a key element of many neurodegenerative disorders [52], especially PD [53,54] and AD [51,55]. The mtDNA is highly vulnerable to oxidative damage and mutation by virtue of its lack of histones, insufficient repair processes [48], and the availability of ROS from increased electron leak of the electron transport chain [56]. While somatic mtDNA mutations contribute to neurodegeneration [51], mtDNA variations give rise to more subtle damage to OXPHOS activity and hence to generation of free radicals [48].

1.2. Nuclear gene variations and mutations in PD The mitochondria as cellular organelles are unique in animal cells as carriers of individual genomes that use transcription factors to interact with the nuclear genome [57] with nuclear gene variations and mutations reported to be associated with PD. Edwards et al. [58] performed a genome-wide association study (GWAS) and confirmed that single nucleotide polymorphisms (SNPs) in SNCA can be common risk factors for PD, as the SNPs in SNCA were associated with susceptibility to PD

Please cite this article as: Andalib S, et al, Parkinson's disease and mitochondrial gene variations: A review, J Neurol Sci (2014), http://dx.doi.org/ 10.1016/j.jns.2014.07.067

S. Andalib et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx

(rs2736990, odds ratio [OR] = 1.29, 95% confidence interval [CI] = 1.17–1.42], p = 0.0109) [58]. The LRRK2 G2019S gene mutation was reported to be a cause of PD in North African Arabs [59]. In 104 unrelated index PD patients, researchers sequenced exon 41, compared to the data from 151 healthy controls. The frequency of the mutation in the Arab population was 37% (10 of 27, 95% CI = 22.4 to 61.2%) in familial cases and 41% (20 of 49, 95% CI = 28.8 to 57.8%) in sporadic cases [59]. Mellick et al. [60] reported one sample of 74 early-onset PD (EOPD) cases out of a cohort of 950 patients (onset b 50 years). Screening showed that two patients carried PARKIN mutations (p.G12R heterozygous and p.G430D homozygous); one patient carried a p.G411S heterozygous amino acid change in the PINK1 gene, and two individuals were heterozygous for the common p.G2019S mutation in LRRK2 [60]. The authors concluded that roughly 7% of the EOPD patients had mutations implicating known PARKIN genes [60]. Lin et al. [61] discussed the importance of the Ala78Thr variant of the ATP13A2 protein, which was located between the highly conserved phosphorylation region and the fifth trans-membrane domain of the ATP13A2 protein. In this study, 182 patients with EOPD and familial PD and 589 matched controls from 2 cohorts of Han Chinese in Taiwan and Singapore were studied. And, sequencing analysis was carried out in the entire ATP13A2 coding region and intron-exon boundaries in 71 probands and 70 controls in the group of Taiwanese and ethnic Chinese subjects. Additional 111 index patients with PD in Singapore and 589 controls were later assessed in order to validate possible mutations explored in the first set of study subjects [61]. One novel missense variant, AL746Thr, was identified in a single heterozygous state in 3 patients (two were from Taiwan and one was from Singapore) (1.7% in EOPD). This variation was not seen in the 589 ethnicity-matched controls. The frequency of the variation in the PD patients was found to be significantly higher than that of the controls in this study (relative risk [RR] = 4.3, 95% CI = 1.9–4.3, p = 0.01) [61]. 1.3. Nuclear gene variations and mutations with mitochondrial dysfunction in PD Recent attention was focused on the role of mitochondrial dysfunction in the pathogenesis of PD [62–64] where mitochondrial dysfunction, metabolic reactions required for OXPHOS, and generation of ATP may fail. A direct link has been shown to exist between the mitochondria and the pathogenesis of PD [37], with mitochondrial electron transport chain dysfunction found to be a primary pathogenic mechanism in early PD [65], and mitochondrial complex I deficiency noted in SN in PD and in platelets [66]. Nuclear genes produce proteins that are imported to the mitochondria and interact within mitochondrial biogenesis where variations and mutations of nuclear genes may contribute to the onset of PD including mitochondrial transcription factor A (TFAM) gene mutations and variations [67]. The nuclear TFAM gene is crucial to ATP production maintenance because it controls the transcription of mtDNA by stabilizing and regulating (or titrating) the amount of mtDNA [67]. Gaweda-Walerych et al. [68] assessed TFAM gene variations in 326 patients with PD and 316 controls and confirmed that rs2306604 G/G of the TFAM gene is an independent risk factor for PD (OR = 1.789, 95% CI = 1.162–2.755, p = 0.008). Mitochondrial defects may also result from mutations of the DJ1 and PINK1 genes and overexpression of SNCA and PARKIN genes. These proteins contribute to the response to oxidative stress and influence proteasomal function potentially leading to PD [3]. Moreover, peroxisome proliferator-activated receptor-γ co-activator (PGC)-1α, a transcriptional co-activator of antioxidant genes, is a regulator of mitochondrial biogenesis and can exert a role in pathogenesis of PD [69]. In this regard, Clark et al. [70] analyzed nuclear DNA from 378 PD patients and 173 age-matched controls by using multiplexed probe sequencing, which was followed by statistical analyses of the

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association of each SNP, alone or in combination along with risk or age of onset of PD. They found possible associations of the PGC-1α SNPs rs6821591 and rs2970848 with risk or age of onset of PD, and of the PGC-1α rs8192678 GG and the rs6821591 CC variants with longevity. POLG (DNA polymerase γ) is a nuclear gene expressing the catalytic subunit of the mtDNA polymerase. The human POLG gene is located on chromosome 15, 15,q25 [71]. Recent evidence suggests that mutations in PLOG gene, which cause impairment of mtDNA replication and in turn mitochondrial dysfunction, may contribute to susceptibility to neurodegenerative diseases such as PD. Early-onset familial PD was demonstrated to stem from PLOG gene mutations in two sisters presenting with dystonic toe curling, action tremor, masked face, bradykinesia, stooped posture, and rigidity, together with clinical and electrophysiological signs of sensorimotor axonal peripheral neuropathy [72]. Increased frequency of rare alleles of the POLG1 CAG-repeat (poly-Q) was seen in Finnish idiopathic and sporadic PD patients [73]; even so, POLG1 poly-Q alleles other than the conserved 10Q allele were found to increase susceptibility in North American Caucasian PD patients [74]. Mancuso et al. [75] assessed a proband, who was a 49-year-old woman with incipient Parkinsonism, and her 59-year-old brother with overt Parkinsonian features and showed multiple mtDNA deletions in the probands' muscle and a novel missense mutation (A2492G) in POLG gene in the proband and her affected siblings. Hudson et al. [76] also claimed that autosomal dominant progressive external ophthalmoplegia (PEO) and Parkinsonism can result from mutations influencing the polymerase domain of POLG directly. 1.4. Mitochondrial DNA variations and mutations in PD Since the discovery of the effect of 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP) on dopaminergic neurons and the specific reduction in the activity of mitochondrial complex I in SN of patients with PD, mitochondrial biochemistry and genetics have garnered serious attentions in the pathogenesis of PD [43]. PD is characterized by a systemic loss of complex I activity in ND ubiquinone oxidoreductase, which is the target enzyme of the PD producing neurotoxin, MPTP [77]. As mentioned above, compared to nuclear DNA, mtDNA is much more susceptible to damage and mutation due to the locally high oxidizing environment of the mitochondria, the relative exposure of mtDNA and the poor mtDNA repair mechanisms [78]. The damage lowers the efficiency of ATP synthesis and raises the generation of reactive waste products [78]. All cells may be affected by this phenomenon, neural cells are particularly vulnerable, and mtDNA mutations, as cause or contributing factor are associated with a number of neurological disorders [78], including Leber's Hereditary Optic Neuropathy (LHON) [79, 80], Myoclonus Epilepsy with Ragged Red Fibers (MERRF) [81,82], Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like episodes (MELAS) [83–85], Kearns–Sayre Syndrome (KSS) [86,87], PEO [88,89], AD [90–92], PD [93], and Multiple Sclerosis (MS) [94,95]. On the other hand, in PD patients, oxidative stress is particularly pronounced in SN pars compacta and that oxidative damage develops in dopaminergic neurons [96], possibly due to increased iron levels, decreased levels of glutathione (GSH), and impaired mitochondrial function [97], especially via decreased complex I activity [98]. More specifically, oxidative damage, including modification of nucleic acids, is involved in dopaminergic neurodegeneration in the SN of patients with PD and the oxidative damage to nucleic acid is largely limited to cytoplasmic RNA and mtDNA as targets [99]. One possible hypothesis of the relationship of mtDNA mutations to observed features of PD addresses the accumulation of somatic mtDNA mutations throughout the body that gives rise to a progressive decline of mitochondrial function [100]. In the brain, cerebral cortex and basal ganglia are sensitive to such a decline because of having the highest rate of somatic mtDNA mutation of any tissue in the body [101] and the dependence on mitochondrial energy production for

Please cite this article as: Andalib S, et al, Parkinson's disease and mitochondrial gene variations: A review, J Neurol Sci (2014), http://dx.doi.org/ 10.1016/j.jns.2014.07.067

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normal function [102]. As a consequence of the declining of the energetics of the neurons, apoptosis fails because of energy failure; and mitochondria with the mutant formylmethionine peptides are released into the extracellular space, where they can be detected as foreign agents engaged in inflammatory responses [100]. A growing body of literature gives evidence of the effect of mtDNA variations in specific populations of patients with PD. Cell metabolism depends on mitochondrial function for energy supply and mtDNA mutations exert an adverse effect upon neuronal function [103]. Huerta et al. [103] studied mtDNA variations and risk of PD in a Spanish population and reported a higher risk of PD among women with the T4336C allele in the tRNA(Gln) gene and a protective role of A10398G against PD. They genotyped 271 cases with PD and 230 healthy controls for 13 SNPs by means of PCR-RFLP (Polymerase Chain ReactionRestriction Fragment Length Polymorphism). Eight SNPs defining nine common European mitochondrial haplogroups were listed by Huerta et al. [103] (Table 1), and no haplogroup was shown to be associated with frequency differences between patients and controls significantly. Moreover, a significant association was observed for the T4336C in the tRNA(Gln) gene, which had a significantly increased frequency in women with PD, compared to controls (OR = 4.45; 95% CI = 1.23–15.96; p = 0.011). Sequencing of five complex I genes (ND1 to ND5) was carried out in the 4336C patients, and no mutation was seen. A significant reduction in the frequency of A10398G in the patients was also reported (OR = 0.53, p = 0.009) [103]. Table 2 lists highly candidated mtDNA variations in association with PD studied in various populations. Bandmann et al. [104] assessed five mtDNA variations involving A3397G, A4336G, G5460A, RsaI site and CofI sites in 100 cases of pathologically proven Caucasian PD patients and 70 healthy controls in UK, but did not observe any significant difference in the frequency of variations between cases and controls, and no contribution of the mtDNA to the PD pathogenesis was confirmed. A PCR-RFLP analysis was performed by Otaegui et al. [105] in order to assess the association between three genetic variations of A4336G, A10398G and T4216C and PD in a Spanish population. The samples were classified by ethnic origin in Basques or other origins. The patients were diagnosed by the Gelb criteria. It was reported that an association existed between A4336G variation in the tRNA(Gln) gene and PD (p = 0.018); nonetheless, lack of association of the T4216C (p = 0.885) and the A10398G (p = 0.088) variations with PD was reported [105]. The mtDNA haplotype 9055G-10398A-13708G contributing to PD susceptibility among Taiwanese individuals older than 70 years was

reported by Chen et al. [106]. The authors assessed the associations of the G9055A, G10398A and G13708A variations to PD in a cohort of 416 PD cases and 372 ethnically matched controls. The allelic frequency for any of these variations was not significantly different between the case and the control groups [106]. None of the six haplotypes had higher risk of PD. Interestingly, subsequent to stratification by age, individuals over 70 years of age having the haplotype 9055G-10398A-13708G showed a significant decline in the PD risk (OR = 0.44, 95% CI = 0.24–0.80, p = 0.008) [106]. Shoffner et al. [107] claimed that PD is a systemic disorder of OXPHOS, perhaps with a complex genetic etiology and that premature cell death in the nigrostriatal dopamine pathway was likely due to energetic impairment and accentuated free radical generation produced by an OXPHOS defect. The authors evaluated deficiencies of OXPHOS enzyme actions and mutations in mtDNA obtained from muscle biopsies of 6 patients afflicted with PD. OXPHOS enzyme assays were then compared to the 5–95% confidence intervals from 16 controls. Four PD patients suffered from complex I defects, and one patient suffered from complex IV defect [107]. A genetic basis for PD was suggested by the findings of this study, owing to the presence of affected relatives of two patients with PD. Specifically, no known mitochondrial DNA mutations (i.e., insertion, deletions, and point mutations) were observed [107]. Ghezzi et al. [108] showed that haplogroup K was likely to pose a lower risk for PD in an Italian population implying that the mitochondrial OXPHOS pathway contributed to the susceptibility to idiopathic PD. The authors assessed the distribution of the different mtDNA haplogroups in a large cohort of 620 Italian patients with adult-onset idiopathic PD and two groups of ethnically matched controls. No significant differences of the frequencies of haplogroup J and 10398G were found. Nevertheless, the frequency of the haplogroup K was significantly lower in PD (0.44, 95% CI = 0.24–0.84) [108]. Van der Walt et al. [109] examined the association of mtDNA variation with PD expression, and genotyped 10 SNPs of European mtDNA haplogroups in 609 white patients with PD and 340 unaffected Caucasian controls. Haplogroup J (OR = 0.55; 95% CI: 0.34–0.91) or K (OR 0.52; 95% CI: 0.30–0.90) demonstrated a significant decrease in the risk of PD compared to subjects carrying the most common haplogroup H [109]. Additionally, 10398G, defining these two haplogroups, was shown to be associated with this protective effect (OR 0.53; 95% CI = 0.39–0.73; p = 0.0001). This variation made a nonconservative amino acid change from threonine to alanine in the NADH dehydrogenase 3 (ND3) of complex I. Subsequent to stratification by

Table 1 Frequencies of the nine mitochondrial haplogroups defined by eight mitochondrial polymorphisms in patients with Parkinson's disease (PD) and healthy controls. (Source: Huerta et al. [103]). Haplogroups H

I

J

K

T

U

V

W

X

G1719A G4580A C7028T G9055A A12308G G13368A G13708A G16391A

G G C G A G G G

A G T G A G G A

G G T G A G A G

G G T A G G G G

G G T G A A G G

G G T G G G G G

G A T G A G G G

G G T G A G G G

A G T G A G G G

PD male N = 125 PD female N = 146 Controls ≥ 55 N = 104 Controls b 55 N = 126

46%

0%

9%

4%

9%

11%

10%

6%

2%

3%

47%

0%

8%

5%

9%

11%

10%

7%

2%

3%

45%

1%

10%

9%

8%

10%

9%

6%

1%

1%

44%

1%

13%

9%

8%

11%

9%

4%

1%

0%

Others

Please cite this article as: Andalib S, et al, Parkinson's disease and mitochondrial gene variations: A review, J Neurol Sci (2014), http://dx.doi.org/ 10.1016/j.jns.2014.07.067

S. Andalib et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx

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Table 2 Highly candidated mitochondrial DNA variations in Parkinson's disease (PD). No.

Variation

Mt gene

The association of mtDNA variations with PD confirmed Author/year

1 2 3

A1438G A3397G T4216C

12sRNA ND1 ND1

4

T4336C

tRNA(Gln)

5

A4336G

tRNA(Gln)

6 7

A4917G G5460A

8 9

Location for population/samples

ND2 ND2

Brown et al., 1996 [114] Ross et al., 2003 [137] Kosel et al., 1998 [135] Kirchner et al., 2000 [140] Huerta et al., 2005 [103] Shoffner et al., 1993 [118] Garcia-Lozano et al., 2002 [119] Egensperger et al., 1997 [120] Otaegui et al., 2004 [105] Kosel et al., 1998 [135] Kosel et al., 1998 [135]

USA Ireland Germany USA Spain USA Spain Germany Spain, Basque Germany Germany

G9055A G10398A

ATP6 ND3

Chen et al. 2007 [106] Chen et al. 2007 [106]

Taiwan Taiwan

10 11 12

A11084G A12308G G13708A

ND4 tRNA(L2) ND5

Takasaki et al., 2008 [122]

Japan

Chen et al. 2007 [106]

Taiwan Germany

13 14 15

G15928A G15950A T15965 C

tRNA(Thr) tRNA(Thr) tRNA(Pro)

Grasbon-Frodl et al., 1999 [121] Grasbon-Frodl et al., 1999 [121] Grasbon-Frodl et al., 1999 [121]

Germany Germany Germany

sex, this decrease in the PD risk was demonstrated to be stronger in women than in men (OR = 0.43, 95% CI = 0.27–0.71, p = 0.0009). The 9055A variation in the ATP6 gene was also found to exert a protective effect for women (OR = 0.45; 95% CI = 0.22–0.93, p = 0.03) [109]. Oxidative stress and consequent energy deficiency, suggested as the cause of nigral neuronal cell loss in PD, was genetically assessed by Ikebe et al. [110]. The authors carried out a direct sequencing of mtDNA in the brains of five PD patients. No predominant point mutations among the patients in contrast to some neuromuscular diseases were reported. However, there were several point mutations in each patient that made a significant change in the resultant proteins. Some of these mutations contributed either to the heightened level of oxygen radicals produced by the mitochondrial respiratory chain or to the higher susceptibility components of the respiratory chain to oxidative damage [110]. The authors concluded that some of these mutations may be risk factors in the degeneration of nigrostriatal pathway of patients with PD.

The association of mtDNA variations with PD not found Author/year

Location for population/samples

Vivez-Bazua et al., 2002 [138] Bandmann et al., 1997 [104] Otaegui et al., 2004 [105] Vivez-Bazua et al., 2002 [138]

Germany UK Spain, Basque Germany

Bandmann et al., 1997 [104] Simon et al., 2000 [139] Houshmand et al., 2007 [123]

UK USA Iran

Vivez-Bazua et al., 2002 [138] Bandmann et al., 1997 [104] Simon et al., 2000 [139]

Germany UK USA

Ghezzi et al., 2005[108] Van der walt et al., 2003 [109] Kosel et al., 1998 [135]

Italy USA Germany

Vivez-Bazua et al., 2002 [138] Otaegui et al., 2004 [105] Vivez-Bazua et al., 2002 [138] Kosel et al., 1998 [135] Simon et al., 2000 [139]

Germany Spain, Basque Germany USA

individual cells, and high levels of these mutations are associated with respiratory chain deficiency [112]. Accumulation of total mtDNA deletions or rearrangements was also demonstrated to be a relatively specific characteristic of PD involved in mitochondrial dysfunction and neurodegeneration in PD in a study performed by Gu et al. [113]. In this study, long-extension polymerase chain reaction (LX-PCR) identified the multiple mtDNA deletions or rearrangements in the SN of patients with PD, multiple system atrophy (MSA), dementia with Lewy bodies (DLB), and AD, compared to agedmatched controls. The total mtDNA deletions or rearrangements in different brain regions of PD patients were studied, demonstrating that both the number and variety of mtDNA deletions or rearrangements were selectively high in the SN of PD patients, compared to patients with other movement disorders as well as patients with AD and agematched controls. Furthermore, increased mtDNA deletions or rearrangements were found in other brain regions in PD patients, showing that mitochondrial dysfunction is not just limited to the SN of PD patients.

1.5. Mitochondrial DNA deletions in PD 1.6. Mitochondrial DNA variations common to both AD and PD In addition to mtDNA mutations and variations, mtDNA deletions affect cellular respiration and raise susceptibility to PD. Evidence from the study of Kraytsberg et al. [111] indicates that mtDNA deletions give rise to functional impairment in aged human SN neurons and to a high proportion of individually pigmented neurons. The authors quantified the total burden of mtDNA molecules with deletions by a novel single-molecule PCR approach and showed that molecules with deletions are largely clonal within each neuron; on another reading, they originate from a single deleted mtDNA molecule that has expanded clonally. They also found that the fraction of mtDNA deletions is significantly high in cytochrome c oxidase (COX)-deficient neurons, compared to COX-positive neurons[111]. Moreover, the findings of Bender et al. [112] corroborated aforementioned results in PD patients and further suggested that somatic mtDNA deletions are crucial in the selective neuronal loss in brain aging and PD. The authors showed that a high level of deleted mtDNA exists in SN neurons in PD compared to controls (controls, 43.3% ± 9.3%; individuals with PD, 52.3% ± 9.3%). It was also claimed that these mtDNA mutations are somatic, with different clonally expanded deletions in

AD and PD, which are late-onset and tissue specific disorders, are genetically heterogeneous and can overlap neuropathologically and clinically [114]. Extrapyramidal signs of PD have been seen in patients afflicted with AD [115,116] and 20–40% of neuropathologically confirmed AD patients' brains were found to have SN degeneration and Lewy body formation in the pigmented nuclei and nucleus basalis (AD plus PD patients) [117]. Such overlap in these diseases may suggest common or related causal factors. There is a growing body of evidence indicating the role of mtDNA variations and mutations in AD and PD. MtDNA variation and mutation at nucleotide pair (np) 4336 located on tRNA(Gln) gene (in close proximity to ND1 gene, but on the opposite strand) has been reported in patients suffering from both AD and PD in numerous populations. Brown et al. [114] studied the mtDNA sequence in three cases with AD presenting with AD plus PD, and one PD patient. The patients' mtDNA sequences were compared to the standard Cambridge sequence to reveal mtDNA mutations. In the first patient suffering from AD and PD, two of the 15 nucleotide changes were involved in the neuropathology [114]. To clarify, the frequency of a transition at

Please cite this article as: Andalib S, et al, Parkinson's disease and mitochondrial gene variations: A review, J Neurol Sci (2014), http://dx.doi.org/ 10.1016/j.jns.2014.07.067

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np 4336 in the tRNA(Gln) gene in the patients was reported to be 7.4 times as great as that of controls. In addition, a unique transition was reported at np 721 in the 12s rRNA gene that was not reported in 70 other patients or 905 controls. Twenty seven nucleotide changes were also observed in the second patient suffering from AD plus PD, incorporating a transition at np 3397 in the ND1 gene converting a conserved methionine to a valine. Two polymorphic base changes frequently seen with high frequency in patients with LHON were observed in the third AD plus PD patient, a transition at np 4216 in ND1 gene and a transition at np 13708 in the ND5 gene. Additionally, two novel mtDNA variations were seen among 25 base changes in the PD patient, a change at np1709 in the 16s rRNA gene and a missense mutation at np 15851 in the cytb gene [114]. In addition, Shoffner et al. [118] assessed mtDNA variations in association with AD plus PD by using PCR-RFLP analysis in a cohort of 71 late-onset Caucasian patients. A variation of A4336G in the tRNA(Gln) gene changing a moderately conserved nucleotide was shown in 5.2% (9/173) of the patients but only in 0.7% of the general Caucasian controls. An additional novel 12S rRNA 5-nucleotide insertion at np 956–965 was present in one of these patients; although a missense variant of A3397G, converting a highly conserved methionine to a valine was observed in the second one. The latter seen in an independent AD plus PD patient, as well as a heteroplasmic 16S rRNA variation of G3196A [118]. MtDNA A4336G mutation as a risk factor for AD plus PD was also investigated in Spanish patients. García-Lozano et al. [119] assessed 161 AD and 106 PD unrelated patients as case group and 78 age-matched and 144 randomly chosen healthy subjects assigned as controls in Spain. It was shown that the A4336G mutation in the tRNA(Gln) gene existed in 1 in 161 patients with AD (0.6%), 3 out of 106 patients with PD (2.8%), 1 in 78 of age-matched healthy controls (1.3%) and 2 out of 144 randomly chosen controls (1.4%) [119]. These results showed a statistically non-significant difference. It was concluded that the results did not confirm the A4336G mutation as a risk factor for either AD or PD patients, at least in the case of this Spanish sample [119]. The role of the mitochondrial A4336G mutation in the tRNA(Gln) gene as a risk factor for AD and PD was suggested by Egensperger et al. [120]. They evaluated the allelic frequencies of A4336G mtDNA variation in 28 neuropathologically confirmed AD patients, 23 cases with Lewy-body PD and 100 age-matched healthy controls. It was reported that A4336G mtDNA variation existed in one of the 28 AD cases and in two out of the 23 PD patients, while no mutation was observed in 100 age-matched controls (P b 0.05) [120]. Grasbon-Frodl et al. [121] argued that mutations in mitochondrial tRNA genes are present in a variety of neurological diseases. The authors also confirmed that A4336G transition of the mitochondrial tRNA(Gln) gene were associated with both AD and PD [121]. In order to assess the association, they carried out a complete sequencing of all 22 mitochondrial tRNA genes in 20 cases that were histologically proven as idiopathic PD. To perform PCR, genomic DNA extracted from the SN of frozen or formalin-fixed and paraffin-embedded brains was utilized and automated sequencing was thereafter done. It was reported that in 1 patient each, 2 new homoplasmic point mutations of G15950A and T15965C existed in the genes for tRNA(Thr) and tRNA(Pro), respectively [121]. RFLP analysis showed absence of the G15950A mutation in 96 controls and 40 cases of AD. The T15965C mutation was found to be absent from the 100 controls and the 47 AD cases [121]. Moreover, it was shown that six known sequence variations were present in a total of 6 different patients in the genes for tRNA(Asp) (G7521A, 1), tRNA(Arg) (T10463C, 1), tRNA(LeuCUN) (A12308G, 2), and tRNA(Thr) (A15924G, 1; G15928A, 2), involving 1 patient with the tRNA(Gln) (A4336G) mutation. The G15950A transition was suggested to exert an impact upon position 70 of the aminoacyl acceptor stem of tRNA(Thr) implicated as a recognition element for threonyl-tRNA synthetase and at least in some tRNAs in the primary mitochondrial transcript processing [121]. The authors also pointed to the role of

T15965C point mutation in the mitochondrial tRNA(Pro) gene changing position 64 of the TpsiC stem; and the corresponding nucleotide in bacterial aminoacyl-tRNAs, which was involved in the interaction with elongation factor Tu. It was concluded that the two novel mutations may be of functional relevance and could be involved in dopaminergic nerve cell death [121]. MtDNA variations of synonymous nucleotide substitutions in addition to those of nonsynonymous nucleotide substitutions involved in mitochondrial functions in Japan were reported by Takasaki [122]. The author assessed the association between mtDNA variations at individual mtDNA positions of the entire mitochondrial genome and three classes of people (96 centenarians, 96 AD patients and 96 PD patients) by means of the radial basis function (RBF) networks. It was mentioned that four amino acid replacements exclusively impacted mitochondrial functions [122]. It was also reported that C5178A (L237M transition at locus ND2) and C8414T (L17F at locus ATP8) variations existed in centenarians; nevertheless, A4833G (T122A at locus ND2) and A11084G (T109A at locus ND4) were associated with AD and PD, respectively [122]. Association of A4336G mtDNA mutation with PD was also assessed in an Iranian population by Houshmand et al. [123]. They investigated mtDNA A4336G mutation and those in the complete regions of ND1, tRNA(leu), ND2 and 16s rRNA by means of sequencing method. Common deletions in the blood samples were also assessed. The evidence from this study suggested that A4336G mtDNA mutation was not associated with the increased risk of PD; nonetheless, other mtDNA mutations may be involved in susceptibility to PD. Lack of association was also reported between mtDNA haplogroups and PD [123]. 1.7. LHON-related mtDNA variations and mutations in PD There are 25 mtDNA variations and mutations specifically associated with the well-documented genetic mitochondrial disorder LHON [124, 125]; be that as it may, three mtDNA mutations at np 3460A, 11778A, and 14484C are specific for LHON and account for 90% of worldwide cases [126]. These three mutations are known as “primary” LHON mutations, impart a partial complex 1 functional deficiency, are seen in multiple affected families, do not typically co-occur with each other, can be homoplasmic or heteroplasmic and are not seen in control mtDNA [126]. However, other primary LHON mtDNA mutations, such as the 14459A and 14495G mutations are observed in more than one LHON family and are rare [127–129]. In addition, a number of “secondary” LHON mtDNA mutations have been identified, and their pathogenicity is less clear [90]. Certain secondary mutations, such as 4216C/ND1, 4917/ND2 and 13708/ND5 affecting mostly complex 1 subunits are found in higher frequencies in LHON patients of European origin than in controls, which highlights the possibility of the contribution to LHON expression as subclinical predisposing factors [126,130–133]. Secondary LHON mtDNA variations and mutations have been reported in MS [94], AD [134] and PD [135], suggesting the association of such mutations with susceptibility to neurodegenerative diseases. T4216C in the ND1 gene, listed as secondary LHON mutation [136], is commonly found in neurodegenerative diseases such as MS [94] and PD. A role for such a variation in the development and pathogenesis of PD was suggested by Ross et al. [137]. The authors claimed that the T4216C variation in linkage with the mtDNA TJ cluster gave rise to mitochondrial dysfunction leading to PD in an Irish population. By means of PCR-RFLP, genetic haplotypes were determined in a cohort of 90 patients with PD. It was demonstrated that no association existed between the various mtDNA haplotypes and PD, compared to healthy aged controls. It was also reported that the longevity-associated European J and T haplogroups were both in tight linkage with the T4216C mtDNA variation [137]. The frequency of the T4216C variation was higher in the PD cases (28%) than in the healthy aged controls (15%) (p = 0.014). Nevertheless, a frequency similar to the PD cases (25%) was seen when the frequency of the T4216C variation was evaluated in a cohort of 200

Please cite this article as: Andalib S, et al, Parkinson's disease and mitochondrial gene variations: A review, J Neurol Sci (2014), http://dx.doi.org/ 10.1016/j.jns.2014.07.067

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young controls (18–45 years). The authors concluded that the frequencies for haplogroups J1, J2, and T in the cohort of PD patients reflected those seen in the young controls used in the previous longevity investigation [137]. The existence of the three certain secondary LHON mutations in PD was confirmed by Kosel et al. [135]. The authors viewed PD not as single disease entity but rather as a genetically heterogeneous group of disorders [135]. The findings implied that 90% or more of all idiopathic PD do not occur because of sequence variation of mitochondrial complex I, and mtDNA mutations are likely to serve a pathogenic role in a subset of PD patients. The authors carried out a complete sequence analysis of all mitochondrial complex I genes in 22 cases of PD. For PCR-based sequencing, the authors used DNA from the SN as a template. Seven novel mutations exchanged amino acids present in subunit genes ND1 (C3992T, A4024G), ND4 (T11253C, C12084T), ND5 (G13711A, T13768C), and ND6 (T14582C) [135]. The authors also found five known missense mutations affecting the ND1 (T3335C, T3338C), ND2 (G5460A), ND3 (A10398G), and ND5 (A13966G) genes, as well as three secondary LHON mutations (T4216C, A4917G, G13708A). Of the novel mutations, the T11253C variation altering a conserved isoleucine residue to threonine was found to have the greatest functional relevance [135]. In addition, 43 synonymous variations were observed in PD brains holding 20 novel sequence variants. Haplogroup analysis assigned the unique missense mutations in the PD patients to the D(c) haplogroup [135]. Several secondary LHON mutations in a study on PD patients and healthy subjects were reported by Vives Bauza et al. [138]. The authors sequenced the entire mtDNA from SN of 8 PD and 9 control subjects and found that several sequence variants were distributed differently between PD and controls, including all previously reported variations (A1438G, A12308G, T4216C, A4917G and G13708A) [138]. In addition to a number of novel missense mutations (T3308G, G5046A, C5194T, G6267A, T7270C, T8504C, A8520G, A11069G, A12074C, C13503G, A13681G, C13702A, A14002G, T14256C, C14766G, A15653G and A15860G), several secondary LHON mutations were observed; nonetheless, all were rare and did not differ between PD patients and controls. It was concluded that PD and control subjects did not differ in the total number of all mutations or the total number of the missense mutations. The mtDNA involvement in PD, if any, was held to be complex and subject to contentious interpretation [138]. Simon et al. [139] argued that mtDNA mutations present in a high percentage of mtDNA molecules of complex I or tRNA genes do not serve a major role in most of PD patients. In addition to RFLP analysis of 243 PD patients and 209 healthy controls for selected mutations, the authors carried out a complete sequencing of all mtDNA-encoded complex I and tRNA genes in 28 PD patients and 8 control subjects. Fifteen complex I missense mutations and 9 tRNA mutations were reported in the PD subjects [139]. The screening also revealed the rare PD patients carrying complex I mutations altering highly conserved amino acids; yet, there were no significant differences in the frequencies of any mutations in the PD patients, in comparison with the control groups. The authors consequently were unable to demonstrate associations of mutations at np 4336, 5460, and 15927/8 with PD. It was also noted that the mutations in complex I gene previously linked to LHON, one of which has been linked to atypical PD, were not correlated with PD [139]. In addition, Kirchner et al. [140] suggested a weak association of T4216C variation with PD [140]. The authors performed an entire ND1 coding region sequencing in 84 PD patients and 127 age- and gendermatched healthy controls in this study and several missense mutations at low frequency (b 5%) were reported in the coding region. Interestingly, missense mutation of thymidine to cytosine at np 4216, replacing tyrosine with histidine, was observed in 25% of the PD subjects, and in 18% of the healthy controls [140]. More to the point, the calculation according to gender showed the T4216C mutation in 26% and 16% of the male cases and controls, respectively (OR = 1.85; 95% CI = 0.79–4.34).

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Nonetheless, the mutation was found in approximately equal frequencies among female cases (22.5%) and controls (21%) yielding an OR of 1.08 (95% CI = 0.36–3.22) [140]. 2. Conclusions The pathogenesis of PD is a complex process, and genetics is held to be an important contributing factor. As mitochondrial dysfunction is involved in the susceptibility to neurodegenerative diseases such as PD, mtDNA variations or mutations may give rise to mitochondrial dysfunction that leads to PD. The association of mtDNA variations and mutations with PD is still tenuous, however, with research focused on the mtDNA variations are also seen in LHON. Thus, numerous investigations suggest an association of secondary LHON mtDNA variations at np 4336, affecting tRNA(Gln) coding region, with susceptibility to PD. There is no general consensus on the validity of this link at present, with data derived from different admixtures of haplogroup populations. The functional consequences of mtDNA variations associated with PD are possible future target of research. For example, neuroimaging is of great interest, as one avenue likely to help shed more light on relation of the pathophysiology of PD to mitochondrial dysfunction. The methods of functional Magnetic Resonance Imaging (fMRI) and Positron Emission Tomography (PET) have helped to map cerebral blood flow and metabolism in vivo in the baseline as well as during functional stimulation. Imaging of studies of this nature will immensely increase the knowledge of mitochondrial genes in PD. Conflict of interest The authors declare that they have no conflict of interest. References [1] Schapira AH. Mitochondria in the aetiology and pathogenesis of Parkinson's disease. Lancet Neurol 2008;7:97–109. [2] de Lau LM, Breteler M. Epidemiology of Parkinson's disease. Lancet Neurol 2006;5: 525–35. [3] Schapira AH. Etiology of Parkinson's disease. Neurology 2006;66:S10–23. [4] Golbe LI, Lazzarini AM, Duvoisin RC, Iorio GD, Sanges G, Bonavita V, et al. Clinical genetic analysis of Parkinson's disease in the Contursi kindred. Ann Neurol 1996; 40:767–75. [5] Jankovic J. Parkinson's disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 2008;79:368–76. [6] Berardelli A, Rothwell JC, Thompson PD, Hallett M. Pathophysiology of bradykinesia in Parkinson's disease. Brain 2001;124:2131–46. [7] Samii A, Nutt JG, Ransom BR. Parkinson's disease. Lancet 2004;363:1783–93. [8] Bronte‐Stewart HM, Minn AY, Rodrigues K, Buckley EL, Nashner LM. Postural instability in idiopathic Parkinson's disease: the role of medication and unilateral pallidotomy. Brain 2002;125:2100–14. [9] Giladi N, Shabtai H, Simon E, Biran S, Tal J, Korczyn A. Construction of freezing of gait questionnaire for patients with Parkinsonism. Parkinsonism Relat Disord 2000;6:165–70. [10] Sapir S, Ramig L, Fox C. Speech and swallowing disorders in Parkinson disease. Curr Opin Otolaryngol Head Neck Surg 2008;16:205–10. [11] Richard IH, Frank S, McDermott MP, Wang H, Justus AW, LaDonna KA, et al. The ups and downs of Parkinson disease: a prospective study of mood and anxiety fluctuations. Cogn Behav Neurol 2004;17:201–7. [12] Chaudhuri K, Healy DG, Schapira AH. Non-motor symptoms of Parkinson's disease: diagnosis and management. Lancet Neurol 2006;5:235–45. [13] Caballol N, Martí MJ, Tolosa E. Cognitive dysfunction and dementia in Parkinson disease. Mov Disord 2007;22:S358–66. [14] Spehlmann R, Stahl S. Dopamine acetylcholine imbalance in Parkinson's disease: possible regenerative overgrowth of cholinergic axon terminals. Lancet 1976; 307:724–6. [15] Davie C. A review of Parkinson's disease. Br Med Bull 2008;86:109–27. [16] Obeso JA, Rodriguez-Oroz MC, Goetz CG, Marin C, Kordower JH, Rodriguez M, et al. Missing pieces in the Parkinson's disease puzzle. Nat Med 2010;16:653–61. [17] Lücking C, Brice A. Alpha-synuclein and Parkinson's disease. Cell Mol Life Sci 2000; 57:1894–908. [18] Schulz-Schaeffer WJ. The synaptic pathology of α-synuclein aggregation in dementia with Lewy bodies, Parkinson's disease and Parkinson's disease dementia. Acta Neuropathol 2010;120:131–43. [19] Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology 2001;57(10):S11–26. [20] Goetz CG, Fahn S, Martinez‐Martin P, Poewe W, Sampaio C, Stebbins GT, et al. Movement disorder society‐sponsored revision of the unified Parkinson's disease

Please cite this article as: Andalib S, et al, Parkinson's disease and mitochondrial gene variations: A review, J Neurol Sci (2014), http://dx.doi.org/ 10.1016/j.jns.2014.07.067

8

S. Andalib et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx

[21] [22] [23] [24] [25]

[26]

[27]

[28]

[29] [30]

[31] [32] [33] [34]

[35]

[36]

[37]

[38]

[39]

[40] [41] [42] [43]

[44]

[45] [46] [47]

[48] [49] [50] [51] [52]

[53] [54]

rating scale (MDS‐UPDRS): process, format, and clinimetric testing plan. Mov Disord 2007;22:41–7. Curtis L, Lees A, Stern G, Marmot M. Effect of L-dopa on course of Parkinson's disease. Lancet 1984;324:211–2. Rinne U, Sonninen V, Siirtola T. Treatment of Parkinson's disease with L-DOPA and decarboxylase inhibitor. Z Neurol 1972;202:1–20. Jenner P. The rationale for the use of dopamine agonists in Parkinson's disease. Neurology 1995;45:S6–S12. Goetz C, Koller W, Poewe W, Rascol O, Sampaio C, Brin M, et al. MAO-B inhibitors for the treatment of Parkinson's disease. Mov Disord 2002;17:S38–44. Farhoudi M, Sadigh-Eteghad S, Andalib S, Vafaee MS, Ziaee M, Mahmoudi J. An analytical review on probable anti-parkinsonian effect of modafinil. J Analyt Res Clin Med 2013;1(2):58–62. Borghammer P, Vafaee M, Ostergaard K, Rodell A, Bailey C, Cumming P. Effect of memantine on CBF and CMRO2 in patients with early Parkinson's disease. Acta Neurol Scand 2008;117:317–23. Vafaee MS, Østergaard K, Sunde N, Gjedde A, Dupont E, Cumming P. Focal changes of oxygen consumption in cerebral cortex of patients with Parkinson's disease during subthalamic stimulation. Neuroimage 2004;22:966–74. Marder K, Tang M-X, Mejia H, Alfaro B, Cote L, Louis E, et al. Risk of Parkinson's disease among first-degree relatives: a community-based study. Neurology 1996; 47:155–60. Payami H, Larsen K, Bernard S, Nutt J. Increased risk of Parkinson's disease in parents and siblings of patients. Ann Neurol 1994;36:659–61. Matsumine H, Saito M, Shimoda-Matsubayashi S, Tanaka H, Ishikawa A, Nakagawa-Hattori Y, et al. Localization of a gene for an autosomal recessive form of juvenile Parkinsonism to chromosome 6q25. 2–27. Am J Hum Genet 1997;60:588. Lesage S, Brice A. Parkinson's disease: from monogenic forms to genetic susceptibility factors. Hum Mol Genet 2009;18:R48–59. Klein C, Schlossmacher MG. The genetics of Parkinson disease: implications for neurological care. Nat Clin Pract Neurol 2006;2:136–46. Henchcliffe C, Beal MF. Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis. Nat Clin Pract Neurol 2008;4:600–9. Paisán-Ruı́z C, Jain S, Evans EW, Gilks WP, Simón J, van der Brug M, et al. Cloning of the gene containing mutations that cause PARK8-Linked Parkinson's disease. Neuron 2004;44:595–600. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, et al. Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science 1997;276:2045–7. Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, et al. Mutations in the parkin gene cause autosomal recessive juvenile Parkinsonism. Nature 1998;392:605–8. Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, et al. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 2004;304:1158–60. Bonifati V, Rizzu P, Squitieri F, Krieger E, Vanacore N, Van Swieten J, et al. DJ-1 (PARK7), a novel gene for autosomal recessive, early onset parkinsonism. Neurol Sci 2003;24:159–60. Ramirez A, Heimbach A, Gründemann J, Stiller B, Hampshire D, Cid LP, et al. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet 2006;38:1184–91. Awadalla P, Eyre-Walker A, Smith JM. Linkage disequilibrium and recombination in hominid mitochondrial DNA. Science 1999;286:2524–5. Chinnery P, Schon E. Mitochondria. J Neurol Neurosurg Psychiatry 2003;74: 1188–99. Giles RE, Blanc H, Cann HM, Wallace DC. Maternal inheritance of human mitochondrial DNA. Proc Natl Acad Sci 1980;77:6715–9. Richter G, Sonnenschein A, Grünewald T, Reichmann H, Janetzky B. Novel mitochondrial DNA mutations in Parkinson's disease. J Neural Transm 2002;109: 721–9. Loeb LA, Wallace DC, Martin GM. The mitochondrial theory of aging and its relationship to reactive oxygen species damage and somatic mtDNA mutations. Proc Natl Acad Sci U S A 2005;102:18769–70. Beal MF. Mitochondria take center stage in aging and neurodegeneration. Ann Neurol 2005;58:495–505. Richter C. Oxidative damage to mitochondrial DNA and its relationship to ageing. Int J Biochem Cell Biol 1995;27:647–53. Inoue M, Sato EF, Nishikawa M, Park A-M, Kira Y, Imada I, et al. Mitochondrial generation of reactive oxygen species and its role in aerobic life. Curr Med Chem 2003; 10:2495–505. Petrozzi L, Ricci G, Giglioli N, Siciliano G, Mancuso M. Mitochondria and neurodegeneration. Biosci Rep 2007;27:87–104. Wei Y-H, Lee H-C. Oxidative stress, mitochondrial DNA mutation, and impairment of antioxidant enzymes in aging. Exp Biol Med 2002;227:671–82. Nunomura A, Honda K, Takeda A, Hirai K, Zhu X, Smith MA, et al. Oxidative damage to RNA in neurodegenerative diseases. BioMed Res Int 2006;2006. Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 2006;443:787–95. Perry G, Nunomura A, Hirai K, Zhu X, Prez M, Avila J, et al. Is oxidative damage the fundamental pathogenic mechanism of Alzheimer's and other neurodegenerative diseases? Free Radic Biol Med 2002;33:1475–9. Jenner P. Oxidative stress in Parkinson's disease. Ann Neurol 2003;53:S26–38. Mizuno Y, Yoshino H, Ikebe S-I, Hattori N, Kobayashi T, Shimoda-Matsubayashi S, et al. Mitochondrial dysfunction in Parkinson's disease. Ann Neurol 1998;44: S99–S109.

[55] Beal MF, Hyman BT, Koroshetz W. Do defects in mitochondrial energy metabolism underlie the pathology of neurodegenerative diseases? Trends Neurosci 1993;16: 125–31. [56] Wei Y-H, Lu C-Y, Lee H-C, Pang C-Y, Ma Y-S. Oxidative damage and mutation to mitochondrial DNA and age‐dependent decline of mitochondrial respiratory function. Ann N Y Acad Sci 1998;854:155–70. [57] Rodell AB, Rasmussen LJ, Bergersen LH, Singh KK, Gjedde A. Natural selection of mitochondria during somatic lifetime promotes healthy aging. Front Neuroenerg 2013;5. [58] Edwards TL, Scott WK, Almonte C, Burt A, Powell EH, Beecham GW, et al. Genomewide association study confirms SNPs in SNCA and the MAPT region as common risk factors for Parkinson disease. Ann Hum Genet 2010;74:97–109. [59] Lesage S, Durr A, Tazir M, Lohmann E, Leutenegger AL, Janin S, et al. LRRK2 G2019S as a cause of Parkinson's disease in North African Arabs. N Engl J Med 2006;354: 422–3. [60] Mellick GD, Siebert GA, Funayama M, Buchanan DD, Li Y, Imamichi Y, et al. Screening PARK genes for mutations in early-onset Parkinson's disease patients from Queensland, Australia. Parkinsonism Relat Disord 2009;15:105–9. [61] Lin CH, Tan EK, Chen ML, Tan LC, Lim HQ, Chen GS, et al. Novel ATP13A2 variant associated with Parkinson disease in Taiwan and Singapore. Neurology 2008;71: 1727–32. [62] Thomas B, Beal MF. Mitochondrial therapies for Parkinson's disease. Mov Disord 2010;25:S155–60. [63] Vila M, Ramonet D, Perier C. Mitochondrial alterations in Parkinson's disease: new clues. J Neurochem 2008;107:317–28. [64] Abou-Sleiman PM, Muqit MM, Wood NW. Expanding insights of mitochondrial dysfunction in Parkinson's disease. Nat Rev Neurosci 2006;7:207–19. [65] Borghammer P, Cumming P, Østergaard K, Gjedde A, Rodell A, Bailey CJ, et al. Cerebral oxygen metabolism in patients with early Parkinson's disease. J Neurol Sci 2012;313:123–8. [66] Gu M, Cooper J, Taanman J, Schapira A. Mitochondrial DNA transmission of the mitochondrial defect in Parkinson's disease. Ann Neurol 1998;44:177–86. [67] Kang D, Kim SH, Hamasaki N. Mitochondrial transcription factor A (TFAM): roles in maintenance of mtDNA and cellular functions. Mitochondrion 2007;7:39–44. [68] Gaweda-Walerych K, Safranow K, Maruszak A, Bialecka M, Klodowska-Duda G, Czyzewski K, et al. Mitochondrial transcription factor: a variants and the risk of Parkinson's disease. Neurosci Lett 2010;469:24–9. [69] Tsunemi T, La Spada AR. PGC-1α at the intersection of bioenergetics regulation and neuron function: from Huntington's disease to Parkinson's disease and beyond. Prog Neurobiol 2012;97:142–51. [70] Clark J, Reddy S, Zheng K, Betensky RA, Simon DK. Association of PGC-1alpha polymorphisms with age of onset and risk of Parkinson's disease. BMC Med Genet 2011;12:69. [71] Ropp PA, Copeland WC. Cloning and characterization of the human mitochondrial DNA polymerase, DNA polymerase gamma. Genomics 1996;36:449–58. [72] Davidzon G, Greene P, Mancuso M, Klos KJ, Ahlskog JE, Hirano M, et al. Early‐onset familial parkinsonism due to POLG mutations. Ann Neurol 2006;59:859–62. [73] Luoma P, Eerola J, Ahola S, Hakonen A, Hellström O, Kivistö K, et al. Mitochondrial DNA polymerase gamma variants in idiopathic sporadic Parkinson disease. Neurology 2007;69:1152–9. [74] Eerola J, Luoma PT, Peuralinna T, Scholz S, Paisan-Ruiz C, Suomalainen A, et al. POLG1 polyglutamine tract variants associated with Parkinson's disease. Neurosci Lett 2010;477:1–5. [75] Mancuso M, Filosto M, Oh SJ, DiMauro S. A novel polymerase γ mutation in a family with ophthalmoplegia, neuropathy, and Parkinsonism. Arch Neurol 2004;61: 1777–9. [76] Hudson G, Schaefer AM, Taylor RW, Tiangyou W, Gibson A, Venables G, et al. Mutation of the linker region of the polymerase γ-1 (POLG1) gene associated with progressive external ophthalmoplegia and Parkinsonism. Arch Neurol 2007;64: 553–7. [77] Parker Jr WD, Parks JK. Mitochondrial ND5 mutations in idiopathic Parkinson's disease. Biochem Biophys Res Commun 2005;326:667–9. [78] Glazner GW. The role of mitochondrial genome mutations in neurodegenerative disease. Adv Cell Aging Gerontol 1999;3:313–54. [79] Yen M-Y, Wang A-G, Chang W-L, Hsu W-M, Liu J-H, Wei Y-H. Leber's hereditary optic neuropathy—the spectrum of mitochondrial DNA mutations in Chinese patients. Jpn J Ophthalmol 2002;46:45–51. [80] Johns DR, Neufeld MJ, Park RD. An ND-6 mitochondrial DNA mutation associated with Leber hereditary optic neuropathy. Biochem Biophys Res Commun 1992; 187:1551–7. [81] Shoffner JM, Lott MT, Lezza AM, Seibel P, Ballinger SW, Wallace DC. Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA(Lys) mutation. Cell 1990;61:931–7. [82] Silvestri G, Moraes C, Shanske S, Oh S, DiMauro S. A new mtDNA mutation in the tRNA (Lys) gene associated with myoclonic epilepsy and ragged-red fibers (MERRF). Am J Hum Genet 1992;51:1213. [83] Tanaka M, Ino H, Ohno K, Ohbayashi T, Ikebe S-i, Sano T, et al. Mitochondrial DNA mutations in mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS). Biochem Biophys Res Commun 1991;174:861–8. [84] Kobayashi Y, Momoi MY, Tominaga K, Momoi T, Nihei K, Yanagisawa M, et al. A point mutation in the mitochondrial tRNA(Leu)(UUR) gene in melas (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes). Biochem Biophys Res Commun 1990;173:816–22. [85] Goto Y-i, Nonaka I, Horai S. A new mtDNA mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Biochim Biophys Acta (BBA) — Mol Basis Dis 1991;1097:238–40.

Please cite this article as: Andalib S, et al, Parkinson's disease and mitochondrial gene variations: A review, J Neurol Sci (2014), http://dx.doi.org/ 10.1016/j.jns.2014.07.067

S. Andalib et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx [86] Carod-Artal F, Lopez GE, Solano A, Dahmani Y, Herrero M, Montoya J. Mitochondrial DNA deletions in Kearns–Sayre syndrome. Neurologia 2006;21:357–64. [87] Nelson I, d'Auriol L, Galibert F, Ponsot G, Lestienne P. Nucleotide mapping and a kinetic model of a heteroplasmic deletion of 4,666 base pairs from mitochondrial DNA in the Kearns–Sayre syndrome. C R Acad Sci III 1988;309:403–7. [88] Goto Y-i, Koga Y, Horai S, Nonaka I. Chronic progressive external ophthalmoplegia: a correlative study of mitochondrial DNA deletions and their phenotypic expression in muscle biopsies. J Neurol Sci 1990;100:63–9. [89] Suomalainen A, Majander A, Wallin M, Setälä K, Kontula K, Leinonen H, et al. Autosomal dominant progressive external ophthalmoplegia with multiple deletions of mtDNA Clinical, biochemical, and molecular genetic features of the 10q-linked disease. Neurology 1997;48:1244–53. [90] Brown MD, Sun F, Wallace DC. Clustering of Caucasian Leber hereditary optic neuropathy patients containing the 11778 or 14484 mutations on an mtDNA lineage. Am J Hum Genet 1997;60:381. [91] de la Monte SM, Luong T, Neely TR, Robinson D, Wands JR. Mitochondrial DNA damage as a mechanism of cell loss in Alzheimer's disease. Lab Invest 2000;80: 1323–35. [92] Corral-Debrinski M, Horton T, Lott MT, Shoffner JM, McKee AC, Beal MF, et al. Marked changes in mitochondrial DNA deletion levels in Alzheimer brains. Genomics 1994;23:471–6. [93] Autere J, Moilanen JS, Finnilä S, Soininen H, Mannermaa A, Hartikainen P, et al. Mitochondrial DNA polymorphisms as risk factors for Parkinson's disease and Parkinson's disease dementia. Hum Genet 2004;115:29–35. [94] Andalib S, Talebi M, Sakhinia E, Farhoudi M, Sadeghi-Bazargani H, Motavallian A, et al. Multiple sclerosis and mitochondrial gene variations: a review. J Neurol Sci 2013;330(1-2):10–5. [95] Mihailova S, Ivanova M, Quin L, Naumova E. Mitochondrial DNA variants in Bulgarian patients affected by multiple sclerosis. Eur J Neurol 2007;14:44–7. [96] Floor E, Wetzel MG. Increased protein oxidation in human substantia nigra pars compacta in comparison with basal ganglia and prefrontal cortex measured with an improved dinitrophenylhydrazine assay. J Neurochem 1998;70:268–75. [97] Jenner P. Oxidative mechanisms in nigral cell death in Parkinson's disease. Mov Disord 1997;13:24–34. [98] Jenner P, Olanow CW. Understanding cell death in Parkinson's disease. Ann Neurol 1998;44:S72–84. [99] Zhang J, Perry G, Smith MA, Robertson D, Olson SJ, Graham DG, et al. Parkinson's disease is associated with oxidative damage to cytoplasmic DNA and RNA in substantia nigra neurons. Am J Pathol 1999;154:1423–9. [100] Coskun P, Wyrembak J, Schriner SE, Chen H-W, Marciniack C, LaFerla F, et al. A mitochondrial etiology of Alzheimer and Parkinson disease. Biochim Biophys Acta Gen Subj 2012;1820:553–64. [101] Corral-Debrinski M, Horton T, Lott MT, Shoffner JM, Beal MF, Wallace DC. Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nat Genet 1992;2:324–9. [102] Wallace DC. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 2005;39: 359. [103] Huerta C, Castro MG, Coto E, Blázquez M, Ribacoba R, Guisasola LM, et al. Mitochondrial DNA polymorphisms and risk of Parkinson's disease in Spanish population. J Neurol Sci 2005;236:49–54. [104] Bandmann O, Sweeney MG, Daniel SE, Marsden CD, Wood NW. Mitochondrial DNA polymorphisms in pathologically proven Parkinson's disease. J Neurol 1997;244: 262–5. [105] Otaegui D, Paisan C, Saenz A, Marti I, Ribate M, Marti-Masso JF, et al. Mitochondrial polymporphisms in Parkinson's disease. Neurosci Lett 2004;370:171–4. [106] Chen CM, Kuan CC, Lee-Chen GJ, Wu YR. Mitochondrial DNA polymorphisms and the risk of Parkinson's disease in Taiwan. J Neural Transm 2007;114: 1017–21. [107] Shoffner JM, Watts RL, Juncos JL, Torroni A, Wallace DC. Mitochondrial oxidative phosphorylation defects in Parkinson's disease. Ann Neurol 1991;30:332–9. [108] Ghezzi D, Marelli C, Achilli A, Goldwurm S, Pezzoli G, Barone P, et al. Mitochondrial DNA haplogroup K is associated with a lower risk of Parkinson's disease in Italians. Eur J Hum Genet 2005;13:748–52. [109] Van der Walt JM, Nicodemus KK, Martin ER, Scott WK, Nance MA, Watts RL, et al. Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease. Am J Hum Genet 2003;72:804–11. [110] Ikebe S-i, Tanaka M, Ozawa T. Point mutations of mitochondrial genome in Parkinson's disease. Mol Brain Res 1995;28:281–95. [111] Kraytsberg Y, Kudryavtseva E, McKee AC, Geula C, Kowall NW, Khrapko K. Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat Genet 2006;38:518–20. [112] Bender A, Krishnan KJ, Morris CM, Taylor GA, Reeve AK, Perry RH, et al. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet 2006;38:515–7. [113] Gu G, Reyes PF, Golden GT, Woltjer RL, Hulette C, Montine TJ, et al. Mitochondrial DNA deletions/rearrangements in parkinson disease and related neurodegenerative disorders. J Neuropathol Exp Neurol 2002;61:634–9. [114] Brown MD, Shoffner JM, Kim YL, Jun AS, Graham BH, Cabell MF, et al. Mitochondrial DNA sequence analysis of four Alzheimer's and Parkinson's disease patients. Am J Med Genet 1996;61:283–9.

9

[115] Chui HC, Teng EL, Henderson VW, Moy AC. Clinical subtypes of dementia of the Alzheimer type. Neurology 1985;35(11):1544. [116] Mayeux R, Stern Y, Spanton S. Heterogeneity in dementia of the Alzheimer type evidence of subgroups. Neurology 1985;35(4):453. [117] Ditter SM, Mirra SS. Neuropathologic and clinical features of Parkinson's disease in Alzheimer's disease patients. Neurology 1987;37(5):754. [118] Shoffner JM, Brown MD, Torroni A, Lott MT, Cabell MF, Mirra SS, et al. Mitochondrial DNA variants observed in Alzheimer disease and Parkinson disease patients. Genomics 1993;17:171–84. [119] García-Lozano JR, Mir P, Alberca R, Aguilera I, Néciga G. Mitochondrial DNA A4336G mutation in Alzheimer's and Parkinson's diseases. Eur Neurol 2002;48:34–6. [120] Egensperger R, Kosel S, Schnopp NM, Mehraein P, Graeber MB. Association of the mitochondrial tRNA(A4336G) mutation with Alzheimer's and Parkinson's diseases. Neuropathol Appl Neurobiol 1997;23:315–21. [121] Grasbon-Frodl EM, Kösel S, Sprinzl M, von Eitzen U, Mehraein P, Graeber MB. Two novel point mutations of mitochondrial tRNA genes in histologically confirmed Parkinson disease. Neurogenetics 1999;2:121–7. [122] Takasaki S. Mitochondrial SNPs associated with Japanese centenarians, Alzheimer's patients, and Parkinson's patients. Comput Biol Chem 2008;32:332–7. [123] Houshmand M, Panahi MSS, Fesahat F, Gharagozli K. Lack of association between mitochondrial A4336G/haplogroup and Parkinson's disease. J Chin Clin Med 2007;2. [124] Brown MD, Zhadanov S, Allen JC, Hosseini S, Newman NJ, Atamonov VV, et al. Novel mtDNA mutations and oxidative phosphorylation dysfunction in Russian LHON families. Hum Genet 2001;109:33–9. [125] Wallace D, Lott M, Brown M, Kerstann K. Mitochondria and neuro-ophthalmological diseases. Metab Mol Basis Inherit Dis 2001;2:2425–512. [126] Brown MD, Starikovskaya E, Derbeneva O, Hosseini S, Allen JC, Mikhailovskaya IE, et al. The role of mtDNA background in disease expression: a new primary LHON mutation associated with Western Eurasian haplogroup J. Hum Genet 2002;110: 130–8. [127] Chinnery P, Brown D, Andrews R, Singh-Kler R, Riordan-Eva P, Lindley J, et al. The mitochondrial ND6 gene is a hot spot for mutations that cause Leber's hereditary optic neuropathy. Brain 2001;124:209–18. [128] Jun AS, Brown MD, Wallace DC. A mitochondrial DNA mutation at nucleotide pair 14459 of the NADH dehydrogenase subunit 6 gene associated with maternally inherited Leber hereditary optic neuropathy and dystonia. Proc Natl Acad Sci 1994;91:6206–10. [129] Jun AS, Trounce IA, Brown MD, Shoffner JM, Wallace DC. Use of transmitochondrial cybrids to assign a complex I defect to the mitochondrial DNA-encoded NADH dehydrogenase subunit 6 gene mutation at nucleotide pair 14459 that causes Leber hereditary optic neuropathy and dystonia. Mol Cell Biol 1996;16:771–7. [130] Lodi R, Montagna P, Cortelli P, Iotti S, Cevoli S, Carelli V, et al. ‘Secondary’ 4216/ND1 and 13708/ND5 Leber's hereditary optic neuropathy mitochondrial DNA mutations do not further impair in vivo mitochondrial oxidative metabolism when associated with the 11778/ND4 mitochondrial DNA mutation. Brain 2000;123:1896–902. [131] Brown MD, Torroni A, Reckord CL, Wallace DC. Phylogenetic analysis of Leber's hereditary optic neuropathy mitochondrial DNA's indicates multiple independent occurrences of the common mutations. Hum Mutat 1995;6:311–25. [132] Howell N, Kubacka I, Halvorson S, Howell B, McCullough DA, Mackey D. Phylogenetic analysis of the mitochondrial genomes from Leber hereditary optic neuropathy pedigrees. Genetics 1995;140:285–302. [133] Torroni A, Petrozzi M, D'Urbano L, Sellitto D, Zeviani M, Carrara F, et al. Haplotype and phylogenetic analyses suggest that one European-specific mtDNA background plays a role in the expression of Leber hereditary optic neuropathy by increasing the penetrance of the primary mutations 11778 and 14484. Am J Hum Genet 1997;60:1107–21. [134] Grazina M, Pratas J, Silva F, Oliveira S, Santana I, Oliveira C. Genetic basis of Alzheimer's dementia: role of mtDNA mutations. Genes Brain Behav 2006;5: 92–107. [135] Kosel S, Grasbon-Frodl EM, Mautsch U, Egensperger R, von Eitzen U, Frishman D, et al. Novel mutations of mitochondrial complex I in pathologically proven Parkinson disease. Neurogenetics 1998;1:197–204. [136] Rozen TD, Shanske S, Otaegui D, Lu J, Young WB, Bradley K, et al. Study of mitochondrial DNA mutations in patients with migraine with prolonged aura. Headache J Head Face Pain 2004;44:674–7. [137] Ross OA, McCormack R, Maxwell LD, Duguid RA, Quinn DJ, Barnett YA, et al. mt4216C variant in linkage with the mtDNA TJ cluster may confer a susceptibility to mitochondrial dysfunction resulting in an increased risk of Parkinson's disease in the Irish. Exp Gerontol 2003;38:397–405. [138] Vives-Bauza C, Andreu AL, Manfredi G, Beal MF, Janetzky B, Gruenewald TH, et al. Sequence analysis of the entire mitochondrial genome in Parkinson's disease. Biochem Biophys Res Commun 2002;290:1593–601. [139] Simon DK, Mayeux R, Marder K, Kowall NW, Beal MF, Johns DR. Mitochondrial DNA mutations in complex I and tRNA genes in Parkinson's disease. Neurology 2000;54: 703–9. [140] Kirchner SC, Hallagan SE, Farin FM, Dilley J, Costa-Mallen P, Smith-Weller T, et al. Mitochondrial ND1 sequence analysis and association of the T4216C mutation with Parkinson's disease. Neurotoxicology 2000;21:441–5.

Please cite this article as: Andalib S, et al, Parkinson's disease and mitochondrial gene variations: A review, J Neurol Sci (2014), http://dx.doi.org/ 10.1016/j.jns.2014.07.067