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Mechanisms of neurodegeneration in idiopathic Parkinson's disease
Parkinsonism & Related Disorders Parkinsonism and Related Disorders 13 (2007) S306–S308 www.elsevier.com/locate/parkreldis
Mechanisms of neurodegeneration in idiopathic Parkinson’s disease J¨org B. Schulz* Department of Neurodegeneration & Restorative Research, Centers for Neurological Medicine and Molecular Physiology of the Brain (CMPB), University Medical Center G¨ottingen, Germany
Abstract The discovery of mutations in hereditary forms of Parkinson’s disease has implicated aggregation of a-synuclein, dysfunction of protein turnover and mitochondrial dysfunction as important mediators in the pathogenesis of Parkinson’s disease. Subsequent studies have shown that these factors also represent hallmarks of idiopathic Parkinson’s disease. Cell death mechanisms include excitotoxicity, calcium overload, apoptosis and autophagia. Here, I will briefly review the molecular mechanisms of neurodegeneration in Parkinson’s disease and point out potential treatment options. © 2007 Elsevier B.V. All rights reserved. Keywords: Parkinson’s disease; Synuclein; Pathogenegsis; Calcium homeostasis; Treatment
1. Introduction The pathogenesis of Parkinson’s disease (PD) is characterized by a loss of dopaminergic neurons, which results in the typical motor control dysfunctions of this movement disorder. Although other brain stem areas, cortical areas, the olfactory bulb and the sympathetic nervous system are affected, the mechanisms of neurodegeneration are best studied in the nigrostriatal system. 2. Synucleinopathy a-Synuclein became a major focus of research into the neurodegeneration of PD since the time that the point mutations (A30P, E46K, A53T) were detected as underlying its hereditary forms. The subsequent demonstration that a-synuclein is the major component of Lewy bodies and Lewy neurites in idiopathic PD as well as dementia with Lewy bodies has put a-synuclein into the spotlight of research into neurodegeneration in general. Point mutations of a-synuclein and its forced expression accelerate fibril formation in test tube assays and in in vitro and in vivo models [1]. Aggregation in neurites occurs before neuronal death and indicates neuronal dysfunction before a loss of neurons can be determined [2]. Which of the fibrillary states of a-synuclein represents the toxic species, however, remains illusive. Physiological a-synuclein consists of a partially * Correspondence: Dept. of Neurodegeneration & Restorative Research, Centers for Neurological Medicine and Molecular Physiology of the Brain (CMPB), University Medical Center G¨ottingen, Waldweg 33, 37073 G¨ottingen, Germany. Tel.: +49 551 39 13540; fax: +49 551 39 13541. E-mail address: [email protected] (J.B. Schulz). 1590-8658/ $ – see front matter © 2007 Elsevier B.V. All rights reserved.
folded auto-inhibited monomer and does not have a random structure as often assumed [3]. The disease-associated point mutations and environmental factors, namely polyamines and copper, that interact with the C-terminus of a-synuclein, destabilize the monomer, disturb its long-range interactions and change the structure to an unfolded state [4–6]. The same is observed with C-terminal truncations. In this state, a-synuclein readily builds up a b-sheet structure, and then forms oligomers and, finally, fibrils. The exact mechanisms of how confirmational changes of a-synuclein induce cell death are currently the subject of intense investigation, but are still poorly understood. It has been suggested that a-synuclein oligomers might form pores on intracellular membranes such as the plasma membrane, and may increase cation permeability. Further mechanisms may include dysfunction of mitochondria, oxidative stress, vesicle processing, synaptic function and protein turnover [7]. The synaptic localization and its supposed synaptic function initially gave synuclein its name. Interestingly, transgenic expression of human or mouse wildtype a-synuclein or of human A53T mutant a-synuclein prevents the neurodegeneration observed in mice deficient for the cysteine-string-protein-a (CSPa), a synaptic vesicle protein with co-chaperone activity thought to prevent accumulation of non-native, potentially toxic molecules during the continuous operation of the nerve terminal [8]. Furthermore, expression of the GPase Rab1, a mediator of the vesicle dynamics, was able to rescue the effects of a-synuclein in yeast and mammalian cell culture [9]. There is also a tight connection between mitochondrial dysfunction and a-synuclein. Firstly, MPTP toxicity increases a-synuclein expression and a-synuclein-deficient
J.B. Schulz / Parkinsonism and Related Disorders 13 (2007) S306–S308
mice are protected from MPTP toxicity [10]. Furthermore, a-synuclein-overexpressing cells and worms appear to be more sensitive to inhibition of complex 1 [11]. As with many other models, it remains an open question why disturbances of a-synuclein specifically lead to toxicity in dopaminergic cells. It has been suggested that synuclein interacts with both the dopamine transporter and the key dopamine synthesis enzyme, tyrosine hydroxylase. Whereas oxidation is believed to increase a-synuclein fibril formation, dopamine itself was shown to inhibit fibrillization, resulting in the formation of a-synuclein spherical oligomers. This inhibition is dependent on dopamine auto-oxidation, but not on a-synuclein oxidation, and the dopamine oxidation product dopaminochrome was identified as a specific inhibitor of a-synuclein fibrillization. Therefore dopamine auto-oxidation can prevent a-synuclein fibrillization and may be protective, whereas the decreased dopamine levels in substantia nigra neurons might promote a-synuclein aggregation in PD [1].
3. Calcium homeostasis and excitotoxicity It has been an attractive hypothesis for decades that excitotoxicity and disturbance in calcium homeostasis are mechanisms leading to neurodegeneration [12]. Glutamate, the major excitatory neurotransmitter in the CNS, induces an increase in the concentration of cytoplasmic calcium by directly activating N-methyl-D-aspartate (NMDA) and a -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor channels and by indirectly activating voltage-dependent calcium channels (VDCC). In addition, normal substantia nigra neuron activity seems to depend on unusually high calcium entry. Treatment with dihydropyridines, specifically isradipine, which has a high affinity for the caV 1.3 subunit of L-type calcium channels, blocked neurodegeneration induced by MPTP, 6-hydroxydopamine and rotenone [13]. Because isradipine is already used in the clinic to treat hypertension, clinical trials may be initiated soon [14]. However, patients with normal blood pressure may react to isradipine with hypotension, thus limiting the use of this medication. Another consequence of disturbed calcium homeostasis is the activation of calpains, a family of cysteine proteases. These are elevated in the mesencephalon of patients with PD but not in other neurodegenerative disorders involving the mesencephalon. David Park and colleagues have shown that calpains are activated and required for MPTP-induced neuronal death in mice [15]. Recently they showed that the activator of Cdk5, p35, may be a critical downstream target for calpains. p35 is proteolytically cleaved to the more active p25 form [16]. The inhibition of calpain leads to reduced p35 to p25 conversion and reduces Cdk5 activation. Park and colleagues were now able to link Cdk5 activation to oxidative stress. They showed that Cdk5-mediated phosphorylation of peroxiredoxin-2 (Prx2)
S307
induces dopaminergic cell death. Peroxiredoxins, along with catalase and glutathione peroxidase, belong to the group of peroxidases that function to eliminate H2 O2 in mammalian cells. Prx2 is located in the cytoplasm of neurons [17]. 4. Apoptosis and autophagy Mitochondrial-dependent apoptotic molecular pathways are involved in MPTP-induced neurodegeneration and likely in the neuronal death associated with the dysfunction of mitochondrial complex 1 in PD. Through oxidative mechanisms the soluble pool of cytochrome C in the mitochondrial intermembrane space is increased. For the release of cytochrome C into the cytosol, an activation and transcriptional induction of Bax to permeabilize the outer mitochondrial membrane appears to be necessary. We recently showed that the tumor suppressor p53 mediates Bax transcriptional induction in MPTP toxicity [18]. Bax mitochondrial translocation relies on the JNK-dependent activation of the BH3-only protein Bim. Therapeutically targeting either transcriptional induction (p53 knockout mice) or mitochondrial translocation of Bax (Bim knockout mice) resulted in a marked attenuation of MPTP-induced dopaminergic cell death. However, striatal dopamine concentrations were not restored. We observed similar results earlier with other anti-apoptotic treatments [19]. Only the gene-therapeutic combination of an anti-apoptotic (neuroprotective) treatment with GDNF (restorative treatment) resulted in full morphological and functional protection. Another cell death mechanism recently implicated in the degeneration of dopaminergic neurons in PD is autophagy. In cells, a-synuclein appears not only to be degraded by the proteasome but also – if not in the majority – by lysosomal enzymes. The chaperone-mediated autophagy, a protein degradation pathway that depends on lysomal function, is affected by dominant a-synuclein mutations [20]. Altered autophagy is also a possible consequence of chronic proteasome inhibition and therefore may be the consequence of other alterations in intact cells. In a cellular model of HtrA2/Omi mutations we identified in PD patients (PARK13), we observed autophagic changes in mitochondria [21]. 5. Conclusion In summary, several interconnected biochemical and molecular pathways result in the degeneration of dopaminergic neurons. Important factors in these pathways appear to be dysregulation of calcium homeostasis, synuclein protein aggregation and mitochondrial dysfunction. Together these lead to excitotoxicity, apoptosis and autophagy. To stop the progression of neuronal death in PD it may be necessary not only to address one of the factors but several of them. Often, achieving effects by addressing several pathways simultaneously requires lower drug concentrations than for a mono-therapy. Clinical trials in the future should address
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J.B. Schulz / Parkinsonism and Related Disorders 13 (2007) S306–S308
multiple treatment targets simultaneously and take into account that PD may not be a homogenous disorder.
Acknowledgements I acknowledge the secretarial assistance of Cathy Ludwig. The work of the author is supported by the German Research Foundation (CMPB) and the Thyssen Foundation.
Conflict of Interest statement None declared.
References [1] Lee VM, Trojanowski JQ. Mechanisms of Parkinson’s disease linked to pathological alpha-synuclein: new targets for drug discovery. Neuron 2006;52:33−8. [2] Kramer ML, Schulz-Schaeffer WJ. Presynaptic alpha-synuclein aggregates, not Lewy bodies, cause neurodegeneration in dementia with Lewy bodies. J Neurosci 2007;27:1405−10. [3] Bertoncini CW, Jung YS, Fernandez CO, Hoyer W, Griesinger C, Jovin TM, et al. Release of long-range tertiary interactions potentiates aggregation of natively unstructured alpha-synuclein. Proc Natl Acad Sci USA 2005;102:1430−5. [4] Bertoncini CW, Fernandez CO, Griesinger C, Jovin TM, Zweckstetter M. Familial mutants of alpha-synuclein with increased neurotoxicity have a destabilized conformation. J Biol Chem 2005;280:30649−52. [5] Fernandez CO, Hoyer W, Zweckstetter M, Jares-Erijman EA, Subramaniam V, Griesinger C, et al. NMR of alpha-synucleinpolyamine complexes elucidates the mechanism and kinetics of induced aggregation. EMBO J 2004;23:2039−46. [6] Rasia RM, Bertoncini CW, Marsh D, Hoyer W, Cherny D, Zweckstetter M, et al. Structural characterization of copper(II) binding to alpha-synuclein: Insights into the bioinorganic chemistry of Parkinson’s disease. Proc Natl Acad Sci USA 2005;102:4294−9. [7] Cookson MR, van der Brug M. Cell systems and the toxic mechanism(s) of alpha-synuclein. Exp Neurol 2007 Jun 4 [Epub ahead of print]. [8] Chandra S, Gallardo G, Fernandez-Chacon R, Schluter OM, Sudhof TC. Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration. Cell 2005;123:383−96.
[9] Cooper AA, Gitler AD, Cashikar A, Haynes CM, Hill KJ, Bhullar B, et al. Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson’s models. Science (New York) 2006;313: 324−8. [10] Dauer W, Kholodilov N, Vila M, Trillat AC, Goodchild R, Larsen KE, et al. Resistance of alpha-synuclein null mice to the parkinsonian neurotoxin MPTP. Proc Natl Acad Sci USA 2002;99:14524−9. [11] Cookson MR. The biochemistry of Parkinson’s disease. Annu Rev Biochem 2005;74:29−52. [12] Mattson MP. Calcium and neurodegeneration. Aging Cell 2007;6: 337−50. [13] Chan CS, Guzman JN, Ilijic E, Mercer JN, Rick C, Tkatch T, et al. ‘Rejuvenation’ protects neurons in mouse models of Parkinson’s disease. Nature 2007;447:1081−6. [14] Sulzer D, Schmitz Y. Parkinson’s disease: return of an old prime suspect. Neuron 2007;55:8−10. [15] Crocker SJ, Smith PD, Jackson-Lewis V, Lamba WR, Hayley SP, Grimm E, et al. Inhibition of calpains prevents neuronal and behavioral deficits in an MPTP mouse model of Parkinson’s disease. J Neurosci 2003;23:4081−91. [16] Smith PD, Crocker SJ, Jackson-Lewis V, Jordan-Sciutto KL, Hayley S, Mount MP, et al. Cyclin-dependent kinase 5 is a mediator of dopaminergic neuron loss in a mouse model of Parkinson’s disease. Proc Natl Acad Sci USA 2003;100:13650−5. [17] Qu D, Rashidian J, Mount MP, Aleyasin H, Parsanejad M, Lira A, et al. Role of Cdk5-mediated phosphorylation of Prx2 in MPTP toxicity and Parkinson’s disease. Neuron 2007;55:37−52. [18] Perier C, Bove J, Wu DC, Dehay B, Choi DK, Jackson-Lewis V, et al. Two molecular pathways initiate mitochondria-dependent dopaminergic neurodegeneration in experimental Parkinson’s disease. Proc Natl Acad Sci USA 2007;104:8161−6. [19] Eberhardt O, von Coelln R, K¨ugler S, Lindenau J, Rathke-Hartlieb S, Gerhardt E, et al. Protection by synergistic effects of adenovirusmediated X-chromosome-linked inhibitor of apoptosis and glial cell line-derived neurotrophic factor gene transfer in the 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. J Neurosci 2000;20:9126−34. [20] Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D. Impaired degradation of mutant alpha-synuclein by chaperonemediated autophagy. Science 2004;305:1292−5. [21] Strauss KM, Martins LM, Plun-Favreau H, Marx FP, Kautzmann S, Berg D, et al. Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson’s disease. Hum Mol Genet 2005;14:2099– 111.
Mechanisms of neurodegeneration in idiopathic Parkinson’s disease J¨org B. Schulz* Department of Neurodegeneration & Restorative Research, Centers for Neurological Medicine and Molecular Physiology of the Brain (CMPB), University Medical Center G¨ottingen, Germany
Abstract The discovery of mutations in hereditary forms of Parkinson’s disease has implicated aggregation of a-synuclein, dysfunction of protein turnover and mitochondrial dysfunction as important mediators in the pathogenesis of Parkinson’s disease. Subsequent studies have shown that these factors also represent hallmarks of idiopathic Parkinson’s disease. Cell death mechanisms include excitotoxicity, calcium overload, apoptosis and autophagia. Here, I will briefly review the molecular mechanisms of neurodegeneration in Parkinson’s disease and point out potential treatment options. © 2007 Elsevier B.V. All rights reserved. Keywords: Parkinson’s disease; Synuclein; Pathogenegsis; Calcium homeostasis; Treatment
1. Introduction The pathogenesis of Parkinson’s disease (PD) is characterized by a loss of dopaminergic neurons, which results in the typical motor control dysfunctions of this movement disorder. Although other brain stem areas, cortical areas, the olfactory bulb and the sympathetic nervous system are affected, the mechanisms of neurodegeneration are best studied in the nigrostriatal system. 2. Synucleinopathy a-Synuclein became a major focus of research into the neurodegeneration of PD since the time that the point mutations (A30P, E46K, A53T) were detected as underlying its hereditary forms. The subsequent demonstration that a-synuclein is the major component of Lewy bodies and Lewy neurites in idiopathic PD as well as dementia with Lewy bodies has put a-synuclein into the spotlight of research into neurodegeneration in general. Point mutations of a-synuclein and its forced expression accelerate fibril formation in test tube assays and in in vitro and in vivo models [1]. Aggregation in neurites occurs before neuronal death and indicates neuronal dysfunction before a loss of neurons can be determined [2]. Which of the fibrillary states of a-synuclein represents the toxic species, however, remains illusive. Physiological a-synuclein consists of a partially * Correspondence: Dept. of Neurodegeneration & Restorative Research, Centers for Neurological Medicine and Molecular Physiology of the Brain (CMPB), University Medical Center G¨ottingen, Waldweg 33, 37073 G¨ottingen, Germany. Tel.: +49 551 39 13540; fax: +49 551 39 13541. E-mail address: [email protected] (J.B. Schulz). 1590-8658/ $ – see front matter © 2007 Elsevier B.V. All rights reserved.
folded auto-inhibited monomer and does not have a random structure as often assumed [3]. The disease-associated point mutations and environmental factors, namely polyamines and copper, that interact with the C-terminus of a-synuclein, destabilize the monomer, disturb its long-range interactions and change the structure to an unfolded state [4–6]. The same is observed with C-terminal truncations. In this state, a-synuclein readily builds up a b-sheet structure, and then forms oligomers and, finally, fibrils. The exact mechanisms of how confirmational changes of a-synuclein induce cell death are currently the subject of intense investigation, but are still poorly understood. It has been suggested that a-synuclein oligomers might form pores on intracellular membranes such as the plasma membrane, and may increase cation permeability. Further mechanisms may include dysfunction of mitochondria, oxidative stress, vesicle processing, synaptic function and protein turnover [7]. The synaptic localization and its supposed synaptic function initially gave synuclein its name. Interestingly, transgenic expression of human or mouse wildtype a-synuclein or of human A53T mutant a-synuclein prevents the neurodegeneration observed in mice deficient for the cysteine-string-protein-a (CSPa), a synaptic vesicle protein with co-chaperone activity thought to prevent accumulation of non-native, potentially toxic molecules during the continuous operation of the nerve terminal [8]. Furthermore, expression of the GPase Rab1, a mediator of the vesicle dynamics, was able to rescue the effects of a-synuclein in yeast and mammalian cell culture [9]. There is also a tight connection between mitochondrial dysfunction and a-synuclein. Firstly, MPTP toxicity increases a-synuclein expression and a-synuclein-deficient
J.B. Schulz / Parkinsonism and Related Disorders 13 (2007) S306–S308
mice are protected from MPTP toxicity [10]. Furthermore, a-synuclein-overexpressing cells and worms appear to be more sensitive to inhibition of complex 1 [11]. As with many other models, it remains an open question why disturbances of a-synuclein specifically lead to toxicity in dopaminergic cells. It has been suggested that synuclein interacts with both the dopamine transporter and the key dopamine synthesis enzyme, tyrosine hydroxylase. Whereas oxidation is believed to increase a-synuclein fibril formation, dopamine itself was shown to inhibit fibrillization, resulting in the formation of a-synuclein spherical oligomers. This inhibition is dependent on dopamine auto-oxidation, but not on a-synuclein oxidation, and the dopamine oxidation product dopaminochrome was identified as a specific inhibitor of a-synuclein fibrillization. Therefore dopamine auto-oxidation can prevent a-synuclein fibrillization and may be protective, whereas the decreased dopamine levels in substantia nigra neurons might promote a-synuclein aggregation in PD [1].
3. Calcium homeostasis and excitotoxicity It has been an attractive hypothesis for decades that excitotoxicity and disturbance in calcium homeostasis are mechanisms leading to neurodegeneration [12]. Glutamate, the major excitatory neurotransmitter in the CNS, induces an increase in the concentration of cytoplasmic calcium by directly activating N-methyl-D-aspartate (NMDA) and a -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor channels and by indirectly activating voltage-dependent calcium channels (VDCC). In addition, normal substantia nigra neuron activity seems to depend on unusually high calcium entry. Treatment with dihydropyridines, specifically isradipine, which has a high affinity for the caV 1.3 subunit of L-type calcium channels, blocked neurodegeneration induced by MPTP, 6-hydroxydopamine and rotenone [13]. Because isradipine is already used in the clinic to treat hypertension, clinical trials may be initiated soon [14]. However, patients with normal blood pressure may react to isradipine with hypotension, thus limiting the use of this medication. Another consequence of disturbed calcium homeostasis is the activation of calpains, a family of cysteine proteases. These are elevated in the mesencephalon of patients with PD but not in other neurodegenerative disorders involving the mesencephalon. David Park and colleagues have shown that calpains are activated and required for MPTP-induced neuronal death in mice [15]. Recently they showed that the activator of Cdk5, p35, may be a critical downstream target for calpains. p35 is proteolytically cleaved to the more active p25 form [16]. The inhibition of calpain leads to reduced p35 to p25 conversion and reduces Cdk5 activation. Park and colleagues were now able to link Cdk5 activation to oxidative stress. They showed that Cdk5-mediated phosphorylation of peroxiredoxin-2 (Prx2)
S307
induces dopaminergic cell death. Peroxiredoxins, along with catalase and glutathione peroxidase, belong to the group of peroxidases that function to eliminate H2 O2 in mammalian cells. Prx2 is located in the cytoplasm of neurons [17]. 4. Apoptosis and autophagy Mitochondrial-dependent apoptotic molecular pathways are involved in MPTP-induced neurodegeneration and likely in the neuronal death associated with the dysfunction of mitochondrial complex 1 in PD. Through oxidative mechanisms the soluble pool of cytochrome C in the mitochondrial intermembrane space is increased. For the release of cytochrome C into the cytosol, an activation and transcriptional induction of Bax to permeabilize the outer mitochondrial membrane appears to be necessary. We recently showed that the tumor suppressor p53 mediates Bax transcriptional induction in MPTP toxicity [18]. Bax mitochondrial translocation relies on the JNK-dependent activation of the BH3-only protein Bim. Therapeutically targeting either transcriptional induction (p53 knockout mice) or mitochondrial translocation of Bax (Bim knockout mice) resulted in a marked attenuation of MPTP-induced dopaminergic cell death. However, striatal dopamine concentrations were not restored. We observed similar results earlier with other anti-apoptotic treatments [19]. Only the gene-therapeutic combination of an anti-apoptotic (neuroprotective) treatment with GDNF (restorative treatment) resulted in full morphological and functional protection. Another cell death mechanism recently implicated in the degeneration of dopaminergic neurons in PD is autophagy. In cells, a-synuclein appears not only to be degraded by the proteasome but also – if not in the majority – by lysosomal enzymes. The chaperone-mediated autophagy, a protein degradation pathway that depends on lysomal function, is affected by dominant a-synuclein mutations [20]. Altered autophagy is also a possible consequence of chronic proteasome inhibition and therefore may be the consequence of other alterations in intact cells. In a cellular model of HtrA2/Omi mutations we identified in PD patients (PARK13), we observed autophagic changes in mitochondria [21]. 5. Conclusion In summary, several interconnected biochemical and molecular pathways result in the degeneration of dopaminergic neurons. Important factors in these pathways appear to be dysregulation of calcium homeostasis, synuclein protein aggregation and mitochondrial dysfunction. Together these lead to excitotoxicity, apoptosis and autophagy. To stop the progression of neuronal death in PD it may be necessary not only to address one of the factors but several of them. Often, achieving effects by addressing several pathways simultaneously requires lower drug concentrations than for a mono-therapy. Clinical trials in the future should address
S308
J.B. Schulz / Parkinsonism and Related Disorders 13 (2007) S306–S308
multiple treatment targets simultaneously and take into account that PD may not be a homogenous disorder.
Acknowledgements I acknowledge the secretarial assistance of Cathy Ludwig. The work of the author is supported by the German Research Foundation (CMPB) and the Thyssen Foundation.
Conflict of Interest statement None declared.
References [1] Lee VM, Trojanowski JQ. Mechanisms of Parkinson’s disease linked to pathological alpha-synuclein: new targets for drug discovery. Neuron 2006;52:33−8. [2] Kramer ML, Schulz-Schaeffer WJ. Presynaptic alpha-synuclein aggregates, not Lewy bodies, cause neurodegeneration in dementia with Lewy bodies. J Neurosci 2007;27:1405−10. [3] Bertoncini CW, Jung YS, Fernandez CO, Hoyer W, Griesinger C, Jovin TM, et al. Release of long-range tertiary interactions potentiates aggregation of natively unstructured alpha-synuclein. Proc Natl Acad Sci USA 2005;102:1430−5. [4] Bertoncini CW, Fernandez CO, Griesinger C, Jovin TM, Zweckstetter M. Familial mutants of alpha-synuclein with increased neurotoxicity have a destabilized conformation. J Biol Chem 2005;280:30649−52. [5] Fernandez CO, Hoyer W, Zweckstetter M, Jares-Erijman EA, Subramaniam V, Griesinger C, et al. NMR of alpha-synucleinpolyamine complexes elucidates the mechanism and kinetics of induced aggregation. EMBO J 2004;23:2039−46. [6] Rasia RM, Bertoncini CW, Marsh D, Hoyer W, Cherny D, Zweckstetter M, et al. Structural characterization of copper(II) binding to alpha-synuclein: Insights into the bioinorganic chemistry of Parkinson’s disease. Proc Natl Acad Sci USA 2005;102:4294−9. [7] Cookson MR, van der Brug M. Cell systems and the toxic mechanism(s) of alpha-synuclein. Exp Neurol 2007 Jun 4 [Epub ahead of print]. [8] Chandra S, Gallardo G, Fernandez-Chacon R, Schluter OM, Sudhof TC. Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration. Cell 2005;123:383−96.
[9] Cooper AA, Gitler AD, Cashikar A, Haynes CM, Hill KJ, Bhullar B, et al. Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson’s models. Science (New York) 2006;313: 324−8. [10] Dauer W, Kholodilov N, Vila M, Trillat AC, Goodchild R, Larsen KE, et al. Resistance of alpha-synuclein null mice to the parkinsonian neurotoxin MPTP. Proc Natl Acad Sci USA 2002;99:14524−9. [11] Cookson MR. The biochemistry of Parkinson’s disease. Annu Rev Biochem 2005;74:29−52. [12] Mattson MP. Calcium and neurodegeneration. Aging Cell 2007;6: 337−50. [13] Chan CS, Guzman JN, Ilijic E, Mercer JN, Rick C, Tkatch T, et al. ‘Rejuvenation’ protects neurons in mouse models of Parkinson’s disease. Nature 2007;447:1081−6. [14] Sulzer D, Schmitz Y. Parkinson’s disease: return of an old prime suspect. Neuron 2007;55:8−10. [15] Crocker SJ, Smith PD, Jackson-Lewis V, Lamba WR, Hayley SP, Grimm E, et al. Inhibition of calpains prevents neuronal and behavioral deficits in an MPTP mouse model of Parkinson’s disease. J Neurosci 2003;23:4081−91. [16] Smith PD, Crocker SJ, Jackson-Lewis V, Jordan-Sciutto KL, Hayley S, Mount MP, et al. Cyclin-dependent kinase 5 is a mediator of dopaminergic neuron loss in a mouse model of Parkinson’s disease. Proc Natl Acad Sci USA 2003;100:13650−5. [17] Qu D, Rashidian J, Mount MP, Aleyasin H, Parsanejad M, Lira A, et al. Role of Cdk5-mediated phosphorylation of Prx2 in MPTP toxicity and Parkinson’s disease. Neuron 2007;55:37−52. [18] Perier C, Bove J, Wu DC, Dehay B, Choi DK, Jackson-Lewis V, et al. Two molecular pathways initiate mitochondria-dependent dopaminergic neurodegeneration in experimental Parkinson’s disease. Proc Natl Acad Sci USA 2007;104:8161−6. [19] Eberhardt O, von Coelln R, K¨ugler S, Lindenau J, Rathke-Hartlieb S, Gerhardt E, et al. Protection by synergistic effects of adenovirusmediated X-chromosome-linked inhibitor of apoptosis and glial cell line-derived neurotrophic factor gene transfer in the 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. J Neurosci 2000;20:9126−34. [20] Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D. Impaired degradation of mutant alpha-synuclein by chaperonemediated autophagy. Science 2004;305:1292−5. [21] Strauss KM, Martins LM, Plun-Favreau H, Marx FP, Kautzmann S, Berg D, et al. Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson’s disease. Hum Mol Genet 2005;14:2099– 111.