α-Synuclein is a pathological link and therapeutic target for Parkinson’s disease and traumatic brain injury

Medical Hypotheses 81 (2013) 675–680

Contents lists available at SciVerse ScienceDirect

Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy

a-Synuclein is a pathological link and therapeutic target for Parkinson’s disease and traumatic brain injury Md Shahaduzzaman a,⇑, Sandra Acosta a, Paula C. Bickford a,b,c, Cesar V. Borlongan a a

Center of Excellence for Aging & Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, USA James A. Haley Veterans Affairs Hospital, Tampa, FL, USA c Department of Molecular Pharmacology and Physiology, University of South Florida, Morsani College of Medicine, Tampa, FL, USA b

a r t i c l e

i n f o

Article history: Received 14 May 2013 Accepted 13 July 2013

a b s t r a c t Parkinson’s disease (PD) affects more than 1% of population over 65 and it is characterized by gradual loss of nigrostriatal dopaminergic neurons and wide spread accumulation of a-synuclein. Collectively 30% of familial and 3–5% of sporadic form of PD are associated with genetic mutation. Compelling evidence implicates that in addition to inherited factors, acquired co-morbidities contribute to PD pathology. Here, we hypothesize that traumatic brain injury (TBI) exacerbates nigrostriatal dopaminergic degeneration by modulating PD-associated genes including a-synuclein, DJ-1, LRRK2, among others. Thus this article will present speculative arguments of a genetic component contributing to this TBI and PD pathological overlap. Published by Elsevier Ltd.

Introduction Over the years epidemiological studies have reported a strong association of traumatic brain injury (TBI) with an increased risk of Parkinson’s disease (PD) [8,19]. However, other studies have contradicted the findings of these epidemiological studies and reported there was no such association between TBI and PD [45,49]. As PD is thought to be a complex multifactorial neurodegenerative disorder, these inconsistencies across studies could be due to the associated conditions such as genetic and environmental risk factors of PD. It could be that the genetically heterogeneous populations enrolled in these studies present with differential susceptibilities to TBI account for these discrepancies. While clinical reports of concussive events (e.g., boxing as in Muhammad Ali’s case leading to PD symptoms) may precede nigrostriatal dopaminergic depletion, the pathological and genetic link between TBI and PD remains poorly understood. Over the past three decades significant advance was made in developing animal models of TBI which demonstrate many fundamental pathophysiological processes relevant to PD etiology [58,62]. Among the many mechanisms implicated in PD pathology, aberrant a-synuclein accumulation has been recognized [56]. Along this line, peripheral nerve injury has been shown to increase accumulation of a-synuclein, which was observed in human CSF and correlated with the secondary neuropathological events following severe TBI [58,47,35]. Of interest, TBI-associated pathologies, such as chronic ⇑ Corresponding author. Address: University of South Florida Morsani College of Medicine, Department of Neurosurgery and Brain Repair, Center of Excellence for Aging and Brain Repair, Tampa, FL, 33612, USA. Tel.: +1 81 397 48222. E-mail address: [email protected] (Md Shahaduzzaman). 0306-9877/$ - see front matter Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.mehy.2013.07.025

traumatic encephalopathy, accompany neurodegeneration, including PD [51,33], providing support to the notion of TBI and PD overlapping pathogenesis. Indeed, exposure to pesticide paraquat combined with TBI leads to triple the risk of PD development [28]. Based on these recent studies, we speculate that TBI modulates PD-associated genes in exacerbating PD symptoms as alluded by previous studies, in particular a-synuclein [57,14], and likely DJ-1 [12,24] and LRRK2 [37]. Unfortunately, we still have major gaps in our understanding of this critical link between TBI and PD. Hypothesis We hypothesize that repeated mild TBI or a severe TBI, especially when combined with targeted PD gene mutations, will magnify the pathological link between TBI and PD (Fig. 1). Our preliminary data suggest an intimate interaction between a-synuclein overexpression and TBI-induced inflammation that may mediate neurodegeneration of the nigrostriatal dopaminergic pathway. We have also observed exacerbation of activated microglial cells in the striatum of both controlled cortical impact (CCI) TBI model and in the 6-hydroxydopamine (6-OHDA) PD model, which demonstrates synergistic effects of a-synuclein and persistent neuroinflammation within the nigrostriatal dopaminergic pathway. These pilot data provide a basis to speculate a close interaction between TBI, genetic predisposition, and PD. Genetic mechanisms and animal models of PD PD is generally a sporadic disease, but a small proportion of cases has a clear genetic component even though genetic

676

Md Shahaduzzaman et al. / Medical Hypotheses 81 (2013) 675–680

Fig. 1. The pathological link between PD and TBI via a-synucleinopathies. TBI may modulate PD-associated genes by exacerbating aberrant protein aggregation. PDassociated genetic mutations promote phosphorylation of a-synuclein by accelerating soluble a-synuclein protofibrils formation (A). Injured neurons after TBI may release soluble a-synuclein that directly impairs mitochondrial function (B) and activates microglia leading to neuroinflammation and oxidative stress which in turn worsen asynuclein aggregation (C). Synergistic effects of a-synuclein aggregation, persistent neuroinflammation, and oxidative stress induced by TBI further disrupt mitochondrial function (D). Altogether a-synuclein serves as the pathological link between PD-associated genetic mutations and TBI exacerbating both PD and TBI pathology. Similar PDassociated protein dysfunctions, such as LRRK2 and DJ-1, may be worsened by TBI that could also lead to more severe impairments in both disease symptoms.

mutations in PD are only about 10% of all PD cases [26]. Studying genetic mechanisms of PD can lead us to identify the common molecular and biochemical pathways involved between the inherited and sporadic forms of PD. A number of transgenic, knockout, and virus-based models of disease have been developed to further understand the pathogenesis, test the potential link and develop therapeutic targets, and how these genes contribute to the pathogenesis of PD. Utilizing these genetic models may allow evaluations of the specific aspects of PD pathogenesis including derangements in dopaminergic synaptic transmission, selective neurodegeneration, neurochemical deficits and protein aggregation-induced neuropathology. Out of six genes causing the six monogenic forms of PD, mutations in a-synuclein and LRRK2 are responsible for autosomal dominant, while mutations in Parkin (PARK2), DJ-1 (PARK7), PINK1 (PARK6), and ATP13A2 (PARK9) are accountable for autosomal recessive PD [48]. Unfortunately, no genetic model has shown all of the pathogenic features of PD characterized by aberrant protein aggregation, DA reduction, and progressive dopaminergic cell death. Although mutations to the a-synuclein genes were the earliest evidence for genetic link to PD, the function and role of a-synuclein in PD is yet to be determined. a-synuclein is a presynaptic neuronal protein thought to play a role in the synaptic vesicle recycling. Two point mutations in the a-synuclein gene (A53T, A30P) are associated with autosomal dominant form of PD [60]. Several transgenic mouse models of a-synuclein gene have been developed, including mice overexpressing a-synuclein, carrying the point mutations of a-synuclein or knockout mice for a-synuclein [7,5]. By overexpressing mutant or wild-type (WT) a-synuclein transgenic animal models have been produced in an effort to recapitulate the pathophysiology of PD. Transgenic models showed a-synuclein produce

inclusions that resemble Lewy bodies in the brain and spinal cord while expression in the substantia nigra was inconsistent [64]. Mutations to the LRRK2 gene, localized to membranes, are the most frequent known cause of late-onset autosomal-dominant form of PD [29]. A recent animal model expressing LRRK2G2019S has been shown to exhibit late-onset and modest loss of DA neurons within the substantia nigra pars compacta in an agedependent manner [41]. LRRK2 rodent models recapitulate an early pathological alteration preceding the loss of nigral neurons thus can be used to explore the interactions between genetic risk and environmental factors that underlie PD etiology. DJ-1 is the third gene associated with PD with 10 different point mutations and associated with 1–2% of early-onset PD cases [26]. DJ-1, also known to PARK7, plays an important role in PD pathogenesis through its antioxidant activity, chaperone-like properties, and transcriptional regulation properties. DJ-1 mutant-carrying patients show the key pathological features of early onset of PD, but do not present with typical late-onset or sporadic PD pathological features such as Lewy bodies [11]. Several attempts were made to create transgenic animal models to recapitulate these early onset PD features, but the animals failed to show clear pathological changes. Most of the DJ-1 KO models do not display robust loss of dopaminergic neurons as well as elevated oxidative stress markers [63,59]. In contrast to knockout models, overexpression of DJ-1 gene not only protected brain from the oxidative damage but also protects the heart as well [25,6]. Recently, a preclinical DJ1-C57 mouse model was generated after backcrossing DJ-1 / mice onto C57BL/6 J background mice which have effectively recapitulated many pathological symptoms of early onset PD including robust unilateral neurodegeneration in substantia nigra compacta as early as two month of age [44]. Most importantly the aged mice of this

Md Shahaduzzaman et al. / Medical Hypotheses 81 (2013) 675–680

model show characteristic loss of dopaminergic neurons in the locus cereolus resembling that of late-onset PD symptoms. Accordingly, we caution that instead of focusing solely on genetics or mere environmental factors, research should consider gene-environment interactions as possible risk factors of PD. Exposure of this DJ1-C57 mouse model to TBI will provide a useful platform for testing gene and environmental interaction and open new avenues to design therapeutic strategies for patients carrying gene mutations with acquired environmental stress factors. Knocking out multiple genes implicated in PD do not demonstrate significant degeneration in the nigrostriatal pathway that resembles idiopathic or inherited PD such as intranuclear inclusions or DA neuron loss, although PINK1 knock-out mice display reduced DA release in the striatum [36]. But recently it was reported that the loss of LRRK2 KO, PINK1 or DJ-1 gene in the rat produces a progressive loss of dopaminergic neurons in the substantia nigra pars compacta at 8-months of age compared to WT [27]. In general, these animal models recapitulate many key features of PD disease, but it is challenging to create a genetic model with all or most of the neuropathological features.

Pathophysiological functions of a-synuclein, LRRK2, and DJ-1, and their interaction with TBI in development of PD

a-Synuclein plays an important role in PD pathogenesis following TBI In humans, a-synuclein is a protein that is encoded by a-synuclein gene which accumulates abnormally in the brain cells in PD patient regardless of the causes. Moreover, the stimulatory factors of soluble a-synuclein aggregation in PD pathogenesis are not well understood. Indeed, a fivefold increase in a-synuclein level in the cerebrospinal fluid immediately after TBI followed by a ten-fold increase on days 4–6 thereafter has been observed in infants and children [52]. The initial increase of a-synuclein in the CSF is thought to be due to the release of soluble a-synuclein from the injured neurons while subsequent a-synuclein increase may be due to altered synaptic transport and release from activated glial cells [52]. Similar to these findings, a-synuclein has also been shown to accumulate in the axonal swellings as well as in the bulb in the traumatized adult brain [57]. Experimental evidence suggests that several mechanisms may potentiate formation of oxidized and nitrated forms of a-synuclein including an inappropriate interaction of a-synuclein with other proteins and oxidative posttranslational modifications [50]. Of interest, a-synuclein elevation by disrupting mitochondrial function upregulates cytosolic calcium, production of free radicals, and activation of calpain, all of which enhance accumulation of cytotoxic a-synuclein [39]. That TBI has been shown to alter mitochondrial function [9] may similarly lead to a-synuclein aggregation and PD symptoms. Moreover, the oxidized form of a-synuclein, considered as the most aggressive type, has been found in the neuronal cytoplasm in patients after TBI [23]. We must also consider aging to play an important role in this pathophysiological process since levels of a-synuclein have been shown to be transiently elevated in aged but not young rats after experimental TBI [58]. Environmental factors and genetic predisposition, such as asynuclein Rep1 expansion, have been recently shown to lead to PD symptoms in a patient with a history of head injury prior to PD diagnosis [18]. The risk of developing PD following head injury appears highly dependent on the variability in the a-synuclein Rep1 genotype in that patients with longer version of Rep1 are more vulnerable to presenting with progressive PD. PD’s characteristic clinical symptoms like tremor, bradykinesia, and rigidity, can be seen following TBI; however, these motor symptoms present differently and generally do not progress in the same manner as

677

PD. Future studies are warranted to assess the interaction of a-synuclein with other genes or environmental factors as they relate to the onset and progression of PD-like motor and cognitive symptoms. A recent study investigating the influence of a-synuclein genetic variants on PD motor symptom progression also shows a faster motor decline in PD patient with longer a-synuclein Rep1 allele (263 bp) [43]. On the contrary, another study has raised the possibility of a dual and opposing role of a-synuclein expression [34]. The research group followed 1,098 Parkinson’s disease patients for 15 years and examined the association of Rep1 genotypes with the PD motor and cognitive outcomes, and reported that while over-expression of a-synuclein increases risk of PD, patients with a reduced expression of shorter allele (259 bp) exhibited severe motor and cognitive outcomes after the disease onset. These findings suggest that therapeutic regimens designed to suppress a-synuclein may increase the severity of PD-associated motor and cognitive deficits in patients already presenting with low levels of a-synuclein expression. Therefore, a careful assessment of multiple genes and environmental factors is necessary in developing treatment programs for PD. Our speculation is that genetic mutations may induce lifelong a-synuclein elevations and may potentiate the risk of PD when combined with TBI-mediated transient elevation of a-synuclein. Interaction of LRRK2 with a-synuclein in the development of PD following TBI Other gene mutations in tandem with a-synuclein accumulation may worsen the neurodegenerative process. It is well established that mutation in LRRK2 and a-synuclein proteins are responsible for autosomal dominant forms of PD [17]. A positive correlation exists between the levels of LRRK2 and phosphorylated and total a-synuclein aggregation in human PD brain extracts [21]. Significant efforts have been made to determine the potential pathogenic interplay between of a-synuclein and LRRK2 in the pathogenesis of PD, documenting their simultaneous upregulation in HEK293 cells under oxidative stress [31] and their co-localization in Lewy bodies, as well as in neurons, in human post mortem PD brains [20,21]. It has been speculated that LRRK2 especially its G2019S kinase-enhancing mutant may promote the phosphorylation of a-synuclein at S129, which may promote formation of asynuclein filaments and oligomers [31]. When LRRK2 is knocked down in a cell culture model, the reduced level of LRRK2 expression coincided with increased number of altered small a-synuclein inclusions [30]. However, neither significant alterations in the levels of phosphorylated a-synuclein nor Lewy body formation and neuronal loss detected both in vitro and in vivo in another study [21]. The nature of LRRK2 and a-synuclein interaction may also involve LRRK2 not only binding with a-synuclein, but additionally forming a protein complex by directly or indirectly binding with other proteins [15]. An impaired autophagy may be another potential mechanism of LRRK2 mediated a-synuclein aggregation as LRRK2 null mice displayed an impaired autophagy function. This finding further supports that mutation in LRRK2 may lose its potential in promoting autophagy system thus resulting in increased accumulation of a-synuclein. Our speculation is that TBI will potentiate this interaction by transiently elevating a-synuclein. Cross-talk between DJ-1 and a-synuclein in the development of PD following TBI Although the protective role of DJ-1 against oxidative stress has been documented in PD, its roles in disease co-morbidities, as well as with other PD gene mutations, are unclear. Several in vitro studies suggest that DJ-1 influences in PD pathogenesis mostly by inhibiting the formation and aggregation of a-synuclein protein

678

Md Shahaduzzaman et al. / Medical Hypotheses 81 (2013) 675–680

Fig. 2. Expression of a-synuclein in the substantia nigra (A) and striatum in an AAV9-synuclein rat PD model. Scale bar = 100 lm.

[46,4]. DJ-1 inactivation by silencing DJ-1 in SK-N-BE cells in vitro revealed an increase a-synuclein aggregation in a cellular model of oxidative stress [4], making SK-N-BE cells more susceptible to oxidative challenge via HSP70 down regulation. The wild type, instead of the mutant DJ-1 (L166P mutant DJ-1), with its chaperon activity effectively inhibits aggregation of a-synuclein fibril by preventing formation of soluble a-synuclein protofibrils [46]. However, an in vivo study demonstrated that lack of DJ-1 did not make mice more vulnerable to a-synuclein toxicity [42]. Nonetheless, studies directed at testing the hypothesis of a cross-talk between DJ-1 and a-synuclein, under oxidative stress-defined brain injuries, like TBI, may better magnify the overlapping disease processes. Growing evidence suggests oxidative stress as pivotal to recognizing DJ-1 associated PD symptoms [25]. To this end, TBI-induced secondary damages have involved production of free radicals which can be ameliorated by reducing levels of ROS [1]. In parallel, DJ-1 has been demonstrated to primarily mediate neuroprotection in both in vitro and in vivo models of stroke where oxidative damage significantly contributes to secondary cell death [3]. With oxidative stress also closely participating in the subsequent brain deterioration after TBI, one can speculate that DJ-1 mutations coupled with a-synuclein may precipitate PD symptoms linking the disease overlapping pathologies [24]. Role of TBI associated inflammatory pathways in the pathogenesis of PD In addition to oxidative stress, there is evidence that inflammation is an equally major secondary cell death in the pathogenesis of PD and TBI. Epidemiological studies support that inflammation has a major impact on toxin-induced as well as genetic models of PD [55]. Pro-inflammatory cytokines including interleukin-1beta (IL1b), interleukin-1beta (IL-1b), and tumor necrosis factor (TNF) have been shown to be elevated in cerebrospinal fluid of patients with PD [55], and that anti-inflammatory drugs reduced the risk of PD development. Our laboratory has reported microglial activation in the striatum and the substantia nigra in animal PD models [38]. Similar to PD, mild-to-moderate TBI induced inflammatory responses immediately after insult which may last month or even years [54]. In our laboratory, we have also observed exacerbation of activated microglial cell in the striatum of both the CCI TBI model and the 6-OHDA PD model [2,22]. We have shown chronic persistent expression of a-synuclein both in substantia nigra and striatum at three months following AAV-9-a-synuclein in a rat PD model (Fig. 2). These above findings strongly suggest that neuroinflammation and a-synuclein expression may potentiate the risk of development of PD following TBI [16]. How TBI-induced neuroinflammation and a-synuclein interact and influence PD neurodegeneration warrants investigations. Striatal microglial activation level positively correlates with the dopaminergic terminal loss in

the putamen [10]. A synergistic effect of a-synuclein and persistent neuroinflammation has been reported an in two-hit mouse model of PD [16]. TBI-induced vicious self-perpetuating glial activation might be the driving force for progressive dopaminergic neurodegeneration [61] as aggregated extracellular a-synuclein activate microglia, which in turn further enhances a-synuclein aggregation [65,40]. Thus, our pilot results are consistent with the hypothesis that TBI may initiate and aggravate degenerative cycle in an environment already stressed by a-synuclein overexpression. Further, TBI could lead to PD symptoms through several cell death mechanisms in addition to direct a-synuclein-mediated toxicity including impaired blood–brain barrier followed by infiltration of immune-inflammatory cells, upregulation of pro-inflammatory cytokines, and glial activation [53]. In the end, the systemic inflammation [13] and oxidative stress induced by TBI and PD, together with inherent gene mutations associated with PD, deserve special consideration in testing the hypothesis of TBI exacerbation of PD pathology [32]. Conclusion Inherited and acquired factors have been implicated in PD pathology. Gene mutations in PD leading to aberrant protein accumulations, such as a-synuclein aggregation, coupled with TBI may synergistically magnify PD symptoms. Our hypothesis advances a pathological link between the genetics of PD and TBI pathophysiology. Laboratory investigations are warranted using genetic PD and TBI models to clarify the overlapping pathogenetic mechanisms between these two disorders. We hypothesize that synucleinopathy is exacerbated by TBI that could accelerate and worsen nigrostriatal dopaminergic depletion via oxidative stress and neuroinflammation. The recognition of this pathological link between TBI and PD will aid in the design of appropriate therapies that can abrogate the gene mutation-induced a-synuclein accumulation (as well as other protein aggregates implicated in PD) and TBI-mediated oxidative stress and neuroinflammation, thereby rendering novel treatment approaches for PD and TBI, and related disorders. Conflict of interest statment All authors disclose no financial conflict of interest to this work. References [1] Abdul-Muneer PM, Schuetz H, Wang F, Skotak M, Jones J, Gorantla S, et al. Induction of oxidative and nitrosative damage leads to cerebrovascular inflammation in an animal model of mild traumatic brain injury induced by primary blast. Free Radic Biol Med 2013;60C:282–91. [2] Acosta SA, Tajiri N, Shinozuka K, Ishikawa H, Grimmig B, Diamond D, et al. Long-term upregulation of inflammation and suppression of cell proliferation

Md Shahaduzzaman et al. / Medical Hypotheses 81 (2013) 675–680

[3]

[4]

[5]

[6]

[7] [8]

[9]

[10]

[11] [12] [13]

[14]

[15]

[16]

[17] [18]

[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26] [27]

[28]

[29] [30]

in the brain of adult rats exposed to traumatic brain injury using the controlled cortical impact model. PLoS One 2013;8(1):e53376. Aleyasin H, Rousseaux MW, Phillips M, Kim RH, Bland RJ, Callaghan S, et al. The Parkinson’s disease gene DJ-1 is also a key regulator of stroke-induced damage. Proc Natl Acad Sci USA 2007;104(47):18748–53. Batelli S, Albani D, Rametta R, Polito L, Prato F, Pesaresi M, et al. DJ-1 modulates alpha-synuclein aggregation state in a cellular model of oxidative stress: relevance for Parkinson’s disease and involvement of HSP70. PLoS One 2008;3(4):e1884. Bezard E, Yue Z, Kirik D, Spillantini MG. Animal models of Parkinson’s disease: limits and relevance to neuroprotection studies. Mov Disord 2013;28(1):61–70. Billia F, Hauck L, Grothe D, Konecny F, Rao V, Kim RH, et al. Parkinsonsusceptibility gene DJ-1/PARK7 protects the murine heart from oxidative damage in vivo. Proc Natl Acad Sci USA 2013;110(15):6085–90. Blesa J, Phani S, Jackson-Lewis V, Przedborski S. Classic and new animal models of Parkinson’s disease. J Biomed Biotechnol 2012;2012:845618. Bower JH, Maraganore DM, Peterson BJ, McDonnell SK, Ahlskog JE, Rocca WA. Head trauma preceding PD: a case-control study. Neurology 2003;60(10):1610–5. Cheng G, Kong RH, Zhang LM, Zhang JN. Mitochondria in traumatic brain injury and mitochondrial-targeted multipotential therapeutic strategies. Br J Pharmacol 2012;167(4):699–719. Choi DY, Liu M, Hunter RL, Cass WA, Pandya JD, Sullivan PG, et al. Striatal neuroinflammation promotes Parkinsonism in rats. PLoS One 2009;4(5):e5482. Corti O, Lesage S, Brice A. What genetics tells us about the causes and mechanisms of Parkinson’s disease. Physiol Rev 2011;91(4):1161–218. Cuny GD. Kinase inhibitors as potential therapeutics for acute and chronic neurodegenerative conditions. Curr Pharm Des 2009;15(34):3919–39. Das M, Mohapatra S, Mohapatra SS. New perspectives on central and peripheral immune responses to acute traumatic brain injury. J Neuroinflammation 2012;9:236. Dayon L, Hainard A, Licker V, Turck N, Kuhn K, Hochstrasser DF, et al. Relative quantification of proteins in human cerebrospinal fluids by MS/MS using 6plex isobaric tags. Anal Chem 2008;80(8):2921–31. Dzamko N, Deak M, Hentati F, Reith AD, Prescott AR, Alessi DR, et al. Inhibition of LRRK2 kinase activity leads to dephosphorylation of Ser(910)/Ser(935), disruption of 14-3-3 binding and altered cytoplasmic localization. Biochem J 2010;430(3):405–13. Gao HM, Zhang F, Zhou H, Kam W, Wilson B, Hong JS. Neuroinflammation and alpha-synuclein dysfunction potentiate each other, driving chronic progression of neurodegeneration in a mouse model of Parkinson’s disease. Environ Health Perspect 2011;119(6):807–14. Gasser T. Mendelian forms of Parkinson’s disease. Biochim Biophys Acta 2009;1792(7):587–96. Goldman SM, Kamel F, Ross GW, Jewell SA, Bhudhikanok GS, Umbach D, et al. Head injury, alpha-synuclein Rep1, and Parkinson’s disease. Ann Neurol 2012;71(1):40–8. Goldman SM, Tanner CM, Oakes D, Bhudhikanok GS, Gupta A, Langston JW. Head injury and Parkinson’s disease risk in twins. Ann Neurol 2006;60(1):65–72. Greggio E, Bisaglia M, Civiero L, Bubacco L. Leucine-rich repeat kinase 2 and alpha-synuclein: intersecting pathways in the pathogenesis of Parkinson’s disease? Mol Neurodegen 2011;6(1):6. Guerreiro PS, Huang Y, Gysbers A, Cheng D, Gai WP, Outeiro TF, et al. LRRK2 interactions with alpha-synuclein in Parkinson’s disease brains and in cell models. J Mol Med (Berl) 2013;91(4):513–22. Hernandez-Ontiveros DG, Tajiri N, Acosta S, Giunta B, Tan J, Borlongan CV. Microglia activation as a biomarker for traumatic brain injury. Front Neurol 2013;4:30. Ikonomovic MD, Uryu K, Abrahamson EE, Ciallella JR, Trojanowski JQ, Lee VM, et al. Alzheimer’s pathology in human temporal cortex surgically excised after severe brain injury. Exp Neurol 2004;190(1):192–203. Jeong HJ, Kim DW, Kim MJ, Woo SJ, Kim HR, Kim SM, et al. Protective effects of transduced Tat-DJ-1 protein against oxidative stress and ischemic brain injury. Exp Mol Med 2012;44(10):586–93. Kahle PJ, Waak J, Gasser T. DJ-1 and prevention of oxidative stress in Parkinson’s disease and other age-related disorders. Free Radic Biol Med 2009;47(10):1354–61. Klein C, Westenberger A. Genetics of Parkinson’s disease. Cold Spring Harb Perspect Med 2012;2(1):a008888. D. Kuldip Dave, S. D. S. Sylvie Ramboz, J. Melissa Beck, Changyu Quang, A. Stanley Benkovic, S. Omar Ahmad et al. (2012). ‘‘MJFF Animal Models 2: Phenotypic characterization of the autosomal recessive (Parkin, Pink-1 and DJ1) gene knockout rat models of Parkinson’s disease’’. Lee PC, Bordelon Y, Bronstein J, Ritz B. Traumatic brain injury, paraquat exposure, and their relationship to Parkinson’s disease. Neurology 2012;79(20):2061–6. Li T, Yang D, Sushchky S, Liu Z, Smith WW. Models for LRRK2-Linked Parkinsonism. Parkinson’s Dis 2011;2011:942412. Lin X, Parisiadou L, Gu XL, Wang L, Shim H, Sun L, et al. Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson’sdisease-related mutant alpha-synuclein. Neuron 2009;64(6):807–27.

679

[31] Liu G, Aliaga L, Cai H. Alpha-synuclein, LRRK2 and their interplay in Parkinson’s disease. Future Neurol 2012;7(2):145–53. [32] Lu J, Goh SJ, Tng PY, Deng YY, Ling EA, Moochhala S. Systemic inflammatory response following acute traumatic brain injury. Front Biosci 2009;14:3795–813. [33] Malpass K. Read all about it! Why TBI is big news. Nat Rev Neurol 2013;9(4):179. [34] Markopoulou, K., J. E. Ahlskog, K. Anderson, S. Armasu, J. Biernacka, S. J. Chung, J. Cunningham, R. Frigerio and D. Maraganore (2013). ‘‘Genetic evidence for a dual and opposing effect of alpha-synuclein expression in preclinical versus clinical Parkinson’s disease (IN2-1.003)’’. Neurology 80 (Meeting Abstracts 1): IN2-1.003. [35] Mondello S, Buki A, Italiano D, Jeromin A. Alpha-Synuclein in CSF of patients with severe traumatic brain injury. Neurology 2013;80(18):1662–8. [36] Moore DJ, Dawson TM. Value of genetic models in understanding the cause and mechanisms of Parkinson’s disease. Curr Neurol Neurosci Rep 2008;8(4):288–96. [37] Mukhida K, Kobayashi NR, Mendez I. A novel role for parkin in trauma-induced central nervous system secondary injury. Med Hypotheses 2005;64(6):1120–3. [38] Pabon MM, Jernberg JN, Morganti J, Contreras J, Hudson CE, Klein RL, et al. A spirulina-enhanced diet provides neuroprotection in an alpha-synuclein model of Parkinson’s disease. PLoS One 2012;7(9):e45256. [39] Protter D, Lang C, Cooper AA. Alpha-synuclein and mitochondrial dysfunction: a pathogenic partnership in Parkinson’s disease? Parkinson’s Dis 2012;2012:829207. [40] Qiao S, Luo JH, Jin JH. Role of microglial activation induced by alpha-synuclein in pathogenesis of Parkinson’s disease. Zhejiang Da Xue Xue Bao Yi Xue Ban 2012;41(2):210–4. [41] Ramonet D, Daher JP, Lin BM, Stafa K, Kim J, Banerjee R, et al. Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2. PLoS One 2011;6(4):e18568. [42] Ramsey CP, Tsika E, Ischiropoulos H, Giasson BI. DJ-1 deficient mice demonstrate similar vulnerability to pathogenic Ala53Thr human alphasyntoxicity. Hum Mol Genet 2010;19(8):1425–37. [43] Ritz B, Rhodes SL, Bordelon Y, Bronstein J. a-Synuclein genetic variants predict faster motor symptom progression in idiopathic Parkinson’s disease. PLoS ONE 2012;7(5):e36199. [44] Rousseaux MW, Marcogliese PC, Qu D, Hewitt SJ, Seang S, Kim RH, et al. Progressive dopaminergic cell loss with unilateral-to-bilateral progression in a genetic model of Parkinson’s disease. Proc Natl Acad Sci USA 2012;109(39):15918–23. [45] Rugbjerg K, Ritz B, Korbo L, Martinussen N, Olsen JH. Risk of Parkinson’s disease after hospital contact for head injury: population based case-control study. BMJ 2008;337:a2494. [46] Shendelman S, Jonason A, Martinat C, Leete T, Abeliovich A. DJ-1 is a redoxdependent molecular chaperone that inhibits alpha-synuclein aggregate formation. PLoS Biol 2004;2(11):e362. [47] Siebert H, Kahle PJ, Kramer ML, Isik T, Schluter OM, Schulz-Schaeffer WJ, et al. Over-expression of alpha-synuclein in the nervous system enhances axonal degeneration after peripheral nerve lesion in a transgenic mouse strain. J Neurochem 2010;114(4):1007–18. [48] Singleton AB, Farrer MJ, Bonifati V. The genetics of Parkinson’s disease: progress and therapeutic implications. Mov Disord 2013;28(1):14–23. [49] Spangenberg S, Hannerz H, Tuchsen F, Mikkelsen KL. A nationwide population study of severe head injury and Parkinson’s disease. Parkinsonism Relat Disord 2009;15(1):12–4. [50] Stefanis L. Alpha-synuclein in Parkinson’s disease. Cold Spring Harb Perspect Med 2012;2(2):a009399. [51] Stern RA, Riley DO, Daneshvar DH, Nowinski CJ, Cantu RC, McKee AC. Longterm consequences of repetitive brain trauma: chronic traumatic encephalopathy. PMR 2011;3(10 Suppl 2):S460–467. [52] Su E, Bell MJ, Wisniewski SR, Adelson PD, Janesko-Feldman KL, Salonia R, et al. Alpha-synuclein levels are elevated in cerebrospinal fluid following traumatic brain injury in infants and children: the effect of therapeutic hypothermia. Dev Neurosci 2010;32(5–6):385–95. [53] Tansey MG, Goldberg MS. Neuroinflammation in Parkinson’s disease: its role in neuronal death and implications for therapeutic intervention. Neurobiol Dis 2010;37(3):510–8. [54] Timaru-Kast R, Luh C, Gotthardt P, Huang C, Schafer MK, Engelhard K, et al. Influence of age on brain edema formation, secondary brain damage and inflammatory response after brain trauma in mice. PLoS One 2012;7(8):e43829. [55] Tufekci KU, Genc S, Genc K. The endotoxin-induced neuroinflammation model of Parkinson’s disease. Parkinson’s Dis 2011;2011:487450. [56] Ulusoy A, Di Monte DA. Alpha-synuclein elevation in human neurodegenerative diseases: experimental, pathogenetic, and therapeutic implications. Mol Neurobiol 2013;47(2):484–94. [57] Uryu K, Chen XH, Martinez D, Browne KD, Johnson VE, Graham DI, et al. Multiple proteins implicated in neurodegenerative diseases accumulate in axons after brain trauma in humans. Exp Neurol 2007;208(2):185–92. [58] Uryu K, Giasson BI, Longhi L, Martinez D, Murray I, Conte V, et al. Agedependent synuclein pathology following traumatic brain injury in mice. Exp Neurol 2003;184(1):214–24.

680

Md Shahaduzzaman et al. / Medical Hypotheses 81 (2013) 675–680

[59] Varcin M, Bentea E, Michotte Y, Sarre S. Oxidative stress in genetic mouse models of Parkinson’s disease. Oxid Med Cell Longev 2012;2012:624925. [60] Wan OW, Chung KK. The role of alpha-synuclein oligomerization and aggregation in cellular and animal models of Parkinson’s disease. PLoS One 2012;7(6):e38545. [61] Wilms H, Rosenstiel P, Romero-Ramos M, Arlt A, Schafer H, Seegert D, et al. Suppression of MAP kinases inhibits microglial activation and attenuates neuronal cell death induced by alpha-synuclein protofibrils. Int J Immunopathol Pharmacol 2009;22(4):897–909.

[62] Xiong Y, Mahmood A, Chopp M. Animal models of traumatic brain injury. Nat Rev Neurosci 2013;14(2):128–42. [63] Yamaguchi H, Shen J. Absence of dopaminergic neuronal degeneration and oxidative damage in aged DJ-1-deficient mice. Mol Neurodegener 2007;2:10. [64] Yasuda T, Nakata Y, Mochizuki H. Alpha-synuclein and neuronal cell death. Mol Neurobiol 2013;47(2):466–83. [65] Zhang W, Wang T, Pei Z, Miller DS, Wu X, Block ML, et al. Aggregated alphasynuclein activates microglia: a process leading to disease progression in Parkinson’s disease. FASEB J 2005;19(6):533–42.