Progress and Prospects in Parkinson's Research/Pathogenesis/Current Parkinson's Paradigm/Role of alpha-synuclein

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Fig 1. Histological sample of Substantia nigra in Parkinson's disease. A. SNpc neuron with a Lewy body, extracellular neuromelanin and pigment-laden macrophages. Haematoxylin/Eosin stain, 500×. B. Alpha-synuclein-positive Lewy neurit, 400×.

Alpha-synuclein is a protein which is firmly associated with Parkinson's pathology.

Proteinaceous inclusions, called Lewy bodies and Lewy neurites occur in neurons in various parts of the brain and of the peripheral nervous system of patients with Parkinson's. (See Fig 1 opposite.) They were discovered in 1912 and were subsequently found to contain a high proportion of aggregated alpha-synuclein.[1]

This page looks at the latest views on the relationship of alpha-synuclein to the pathogenesis of Parkinson's.

Braak Staging theory[edit | edit source]

Fig 2. Staging of Lewy pathology according to the Braak model. Schematic summarizing the progression of Parkinson’s disease as proposed by Braak and colleagues [1]. According to the Braak model, αsyn deposits in specific brain regions and neuronal types giving rise to Lewy pathology in a stereotypic, temporal pattern that ascends caudo-rostrally from the lower brainstem (including the dorsal motor nucleus of the vagus nerve in the medulla then the coeruleus-subcoeruleus complex, raphe nuclei, gigantocellular reticular nucleus in the medulla aand pons) through susceptible regions of the midbrain (substantia nigra and the pedunculopontine tegmental nucleus) and forebrain (e.g., amygdala) and into the cerebral cortex (e.g., anteromedial temporal mesocortex, cingulate cortex and later neocortical structures). It is hypothesized that the disease initiates in the periphery, gaining access to the CNS through retrograde transport along projection neurons from the gastrointestinal tract. As the disease progresses, the severity of lesions in the susceptible regions increases.

In work done over ten years ago, Heiko Braak et al examined the alpha-synuclein pathology in the brains of Parkinson's patients. This led to their proposing the staging hypothesis of Parkinson's progression[2]. (See Fig 2 opposite.) This stimulated a huge interest in the neuropatholigical role of this protein.

The Wikipedia page on Parkinson's disease describes the Staging Hypothesis as follows:

According to the Braak staging, a classification of the disease based on pathological findings, Lewy bodies first appear in the olfactory bulb, medulla oblongata and pontine tegmentum, with individuals at this stage being asymptomatic. As the disease progresses, Lewy bodies later develop in the substantia nigra, areas of the midbrain and basal forebrain, and in a last step the neocortex.

Despite critical assessment (eg [3]), the hypothesis is now accepted as a largely valid account[4] of the way that alpha-synuclein pathology spreads through the brain in idiopathic Parkinson's.

The origin of the pathological process, which may well be in the peripheral nervous system, and the mechanism by which it is conveyed from one area to another, are currently the subject of great scrutiny.

Abnormal alpha-synuclein in the Parkinsonian brain[edit | edit source]

The normal role of alpha-synuclein still remains to be fully elucidated. In its physiological form alpha-synuclein is a small, natively-unfolded protein which has a role in the transport mechanism within cells. Presumably the usual garbage collection processes [5](the Ubiquitin Proteasome System (UPS) and autophagy) normally take care of any misfolding, denaturing and aggregation that take place as a result of normal metabolism. The sections below will discuss what appears to happen when these mechanisms are inadequate and what might cause the pathological process to be initiated in first place.

In Parkinson's the pathological process once established challenges, and even damages, the normal homeostatic mechanisms involving the innate and adaptive immune systems, the UPS and autophagy. Mitochondrial function is also affected and apoptosis in vulnerable neurons is triggered. It appears that a self-reinforcing pathogenic process is established but this, perhaps surprisingly, does not accelerate to an acute, fatal end-point. (In Multiple System Atrophy, by contrast, the disease process is faster and is inevitably terminal within 10 years on average.) Perhaps the slowness of the cell to cell transmission of the pathogenesis provides a restraint. Nevertheless the different parts of the nervous system are only slowly affected and it usually takes many years for the pattern of motor and non-motor symptoms of Parkinson's to develop fully.

Other neurodegenerative diseases including Multiple System Atrophy, Dementia with Lewy bodies[6] and Alzheimer's also involve alpha-synuclein pathology. Why the aggregation in such diseases affects different cell types awaits an answer.

Fig 3. Events in α-synuclein toxicity. The central panel shows the major pathway for protein aggregation. Monomeric α-synuclein is natively unfolded in solution but can also bind to membranes in an α-helical form. It seems likely that these two species exist in equilibrium within the cell, although this is unproven. From in vitro work, it is clear that unfolded monomer can aggregate first into small oligomeric species that can be stabilized by β-sheet-like interactions and then into higher molecular weight insoluble fibrils. In a cellular context, there is some evidence that the presence of lipids can promote oligomer formation: α-synuclein can also form annular, pore-like structures that interact with membranes. The deposition of α-synuclein into pathological structures such as Lewy bodies is probably a late event that occurs in some neurons. On the left hand side are some of the known modifiers of this process. Electrical activity in neurons changes the association of α-synuclein with vesicles and may also stimulate polo-like kinase 2 (PLK2), which has been shown to phosphorylate α-synuclein at Ser129. Other kinases have also been proposed to be involved. As well as phosphorylation, truncation through proteases such as calpains, and nitration, probably through nitric oxide (NO) or other reactive nitrogen species that are present during inflammation, all modify synuclein such that it has a higher tendency to aggregate. The addition of ubiquitin (shown as a black spot) to Lewy bodies is probably a secondary process to deposition. On the right are some of the proposed cellular targets for α-synuclein mediated toxicity, which include (from top to bottom) ER-golgi transport, synaptic vesicles, mitochondria and lysosomes and other proteolytic machinery. In each of these cases, it is proposed that α-synuclein has detrimental effects, listed below each arrow, although at this time it is not clear if any of these are either necessary or sufficient for toxicity in neurons. [7]


Propensity to aggregate[edit | edit source]

Greenbaum et al (2005) state:

The finding that soluble recombinant alpha-synuclein readily polymerizes into ~10-nm filaments in vitro has provided critical evidence supporting the notion that alpha-synuclein is the building block of Lewy bodies and related pathological inclusions.[8]

The propensity for alpha-synuclien to aggregate is increased by:

  • mere overexpression
This occurs, for instance, when the gene which produces the protein duplicated or triplicated.[9]
  • modification by oxidation, nitration and phosphorylation[10]
  • inflammation
Inflammation and aggregation of α-syn are dynamically interlinked[11]
  • genetic variation[10]

The review by Stefanis (2012) [10], “α-Synuclein in Parkinson’s Disease”, gives a good account of these factors.

Lewy bodies and Lewy neurites are the ultimate products of α-synuclein aggregation. The process proceeds through fibril formation but, as Stefanis says, "in the process of fibril formation various intermediate forms of α-synuclein develop. These are initially soluble oligomeric forms of α-synuclein". It is the soluble oligomers which are believed to be the toxic species.[12] See also Fig 3 opposite.[7]

Pro-inflammatory nature of abnormal alpha-synuclein[edit | edit source]

A recent key review is Béraud et al, “Microglial Activation and Antioxidant Responses Induced by the Parkinson’s Disease Protein Α-synuclein.” (2012/13)[13]

Other key papers:

Hwang, Onyou. “Role of Oxidative Stress in Parkinson’s Disease.” Experimental Neurobiology 22, no. 1 (March 2013): 11–17. doi:10.5607/en.2013.22.1.11. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3620453/

Lema Tome, Carla M., Trevor Tyson, Nolwen L. Rey, Stefan Grathwohl, Markus Britschgi, and Patrik Brundin. “Inflammation and ?-Synuclein’s Prion-like Behavior in Parkinson’s Disease--Is There a Link?” Molecular Neurobiology 47, no. 2 (April 2013): 561–574. doi:10.1007/s12035-012-8267-8. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3589652/

Gao, Hui-Ming, Feng Zhang, Hui Zhou, Wayneho Kam, Belinda Wilson, and Jau-Shyong Hong. “Neuroinflammation and α-Synuclein Dysfunction Potentiate Each Other Driving Chronic Progression of Neurodegeneration in a Mouse Model of Parkinson’s Disease.” Environmental Health Perspectives (January 2011). doi:10.1289/ehp.1003013. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3114815/

Qian, Li, Patrick M Flood, and Jau-Shyong Hong. “Neuroinflammation Is a Key Player in Parkinson’s Disease and a Prime Target for Therapy.” Journal of Neural Transmission (Vienna, Austria: 1996) 117, no. 8 (August 2010): 971–979. doi:10.1007/s00702-010-0428-1. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3392895/

Gao, Hui-Ming, Paul T Kotzbauer, Kunihiro Uryu, Susan Leight, John Q Trojanowski, and Virginia M-Y Lee. “Neuroinflammation and Oxidation/nitration of Alpha-synuclein Linked to Dopaminergic Neurodegeneration.” The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 28, no. 30 (July 23, 2008): 7687–7698. doi:10.1523/JNEUROSCI.0143-07.2008. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2702093/




(**Continue from here**)



Draft contents continued

(Not necessarily in this order)

Progression through nervous system - prion-like behaviour[14][15]

The toxic species[7]

Oxidation, nitrosation and phosphorylation

The 'normal' role of a-syn

The 'normal' conformation of the protein

Variations in SNCA gene [16]

Inflammation and the immune response[17][18]

Alternative splicing

UPS and autophagy

Relationship to mitochondrial dysfunction[19]

Treatment strategies, pros and cons[18]


References[edit | edit source]

  1. ↑ Shults, Clifford W. “Lewy Bodies.” Proceedings of the National Academy of Sciences of the United States of America 103, no. 6 (February 7, 2006): 1661–1668. doi:10.1073/pnas.0509567103. http://www.pnas.org/content/103/6/1661.full.
  2. ↑ Braak, Heiko, Kelly Del Tredici, Udo Rüb, Rob A I de Vos, Ernst N H Jansen Steur, and Eva Braak. “Staging of Brain Pathology Related to Sporadic Parkinson’s Disease.” Neurobiology of Aging 24, no. 2 (April 2003): 197–211. http://neuro.pathology.pitt.edu/webstuff/AD%20J%20Club%20papers/StagingPDpathBraaks.pdf.
  3. ↑ Burke, Robert E., William T. Dauer, and Jean Paul G. Vonsattel. “A Critical Evaluation of The Braak Staging Scheme for Parkinson’s Disease.” Annals of Neurology 64, no. 5 (November 2008): 485–491. doi:10.1002/ana.21541.“PubMed Central Full Text PDF.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2605160/pdf/nihms-74730.pdf.
  4. ↑ Dickson, Dennis W, Hirotake Uchikado, Hiroshige Fujishiro, and Yoshio Tsuboi. “Evidence in Favor of Braak Staging of Parkinson’s Disease.” Movement Disorders: Official Journal of the Movement Disorder Society 25 Suppl 1 (2010): S78–82. doi:10.1002/mds.22637. http://www.ncbi.nlm.nih.gov/pubmed/20187227
  5. ↑ Webb, Julie L, Brinda Ravikumar, Jane Atkins, Jeremy N Skepper, and David C Rubinsztein. “Alpha-Synuclein Is Degraded by Both Autophagy and the Proteasome.” The Journal of Biological Chemistry 278, no. 27 (July 4, 2003): 25009–25013. doi:10.1074/jbc.M300227200. http://www.jbc.org/content/278/27/25009.long
  6. ↑ Spillantini, M G, R A Crowther, R Jakes, N J Cairns, P L Lantos, and M Goedert. “Filamentous Alpha-synuclein Inclusions Link Multiple System Atrophy with Parkinson’s Disease and Dementia with Lewy Bodies.” Neuroscience Letters 251, no. 3 (July 31, 1998): 205–208. http://www.ncbi.nlm.nih.gov/pubmed/9726379/
  7. ↑ 7.0 7.1 7.2 Diagram from: Cookson, Mark. “alpha-Synuclein and Neuronal Cell Death.” Molecular Neurodegeneration 4, no. 1 (2009): 9. doi:10.1186/1750-1326-4-9. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2646729/.
  8. ↑ Greenbaum, Eric A., Charles L. Graves, Amanda J. Mishizen-Eberz, Michael A. Lupoli, David R. Lynch, S. Walter Englander, Paul H. Axelsen, and Benoit I. Giasson. “The E46K Mutation in α-Synuclein Increases Amyloid Fibril Formation.” Journal of Biological Chemistry 280, no. 9 (March 4, 2005): 7800–7807. doi:10.1074/jbc.M411638200. http://www.jbc.org/content/280/9/7800.full.pdf+html
  9. ↑ Singleton, A B, M Farrer, J Johnson, A Singleton, S Hague, J Kachergus, M Hulihan, et al. “alpha-Synuclein Locus Triplication Causes Parkinson’s Disease.” Science (New York, N.Y.) 302, no. 5646 (October 31, 2003): 841. doi:10.1126/science.1090278. http://www.ncbi.nlm.nih.gov/pubmed/14593171 See also Singleton et al http://www.ncbi.nlm.nih.gov/pubmed/15159488.
  10. ↑ 10.0 10.1 10.2 Stefanis L. “α-Synuclein in Parkinson’s Disease, Cold Spring Harb Perspect Med. 2012 February; 2(2): a009399. doi: 10.1101/cshperspect.a009399. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281589 For protein modification see: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281589/#s6title For genetic variation see: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281589/#s1title
  11. ↑ Lema Tome, Carla M., Trevor Tyson, Nolwen L. Rey, Stefan Grathwohl, Markus Britschgi, and Patrik Brundin. “Inflammation and α-Synuclein’s Prion-like Behavior in Parkinson’s Disease--Is There a Link?” Molecular Neurobiology 47, no. 2 (April 2013): 561–574. doi:10.1007/s12035-012-8267-8. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3589652/#Sec3title
  12. ↑ Winner, Beate, Roberto Jappelli, Samir K. Maji, Paula A. Desplats, Leah Boyer, Stefan Aigner, Claudia Hetzer, et al. “In Vivo Demonstration That ?-synuclein Oligomers Are Toxic.” Proceedings of the National Academy of Sciences of the United States of America 108, no. 10 (March 8, 2011): 4194–4199. doi:10.1073/pnas.1100976108. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3053976/.
  13. ↑ Béraud, Dawn, Hannah A Hathaway, Jordan Trecki, Sergey Chasovskikh, Delinda A Johnson, Jeffrey A Johnson, Howard J Federoff, Mika Shimoji, Timothy R Mhyre, and Kathleen A Maguire-Zeiss. “Microglial Activation and Antioxidant Responses Induced by the Parkinson’s Disease Protein Α-synuclein.” Journal of Neuroimmune Pharmacology: The Official Journal of the Society on NeuroImmune Pharmacology 8, no. 1 (March 2013): 94–117. doi:10.1007/s11481-012-9401-0. “Microglial Activation and Antioxidant Responses Induced by the Parkinson’s Disease Protein α-Synuclein.” Accessed June 12, 2013. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3582877/
  14. ↑ Alpha-syn in peripheral nervous systemLema Tome, Carla M., Trevor Tyson, Nolwen L. Rey, Stefan Grathwohl, Markus Britschgi, and Patrik Brundin. “Inflammation and ?-Synuclein’s Prion-like Behavior in Parkinson’s Disease--Is There a Link?” Molecular Neurobiology 47, no. 2 (April 2013): 561–574. doi:10.1007/s12035-012-8267-8. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3589652/
  15. ↑ George, Sonia, Nolwen L. Rey, Nicole Reichenbach, Jennifer A. Steiner, and Patrik Brundin. “α-Synuclein: The Long Distance Runner.” Brain Pathology 23, no. 3 (2013): 350–357. doi:10.1111/bpa.12046. http://onlinelibrary.wiley.com/doi/10.1111/bpa.12046/full.
  16. ↑ Venda, Lara Lourenco, Stephanie J. Cragg, Vladimir L. Buchman, and Richard Wade-Martins. “α-Synuclein and Dopamine at the Crossroads of Parkinson’s Disease.” Trends in Neurosciences 33, no. 12 (December 2010): 559–568. doi:10.1016/j.tins.2010.09.004. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3631137/
  17. ↑ Glass, Christopher K., Kaoru Saijo, Beate Winner, Maria Carolina Marchetto, and Fred H. Gage. “Mechanisms Underlying Inflammation in Neurodegeneration.” Cell 140, no. 6 (March 19, 2010): 918–934. doi:10.1016/j.cell.2010.02.016. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2873093/
  18. ↑ 18.0 18.1 Hirsch, Etienne C, and Stéphane Hunot. “Neuroinflammation in Parkinson’s Disease: a Target for Neuroprotection?” Lancet Neurology 8, no. 4 (April 2009): 382–397. doi:10.1016/S1474-4422(09)70062-6.
  19. ↑ McCoy, Melissa K., and Mark R. Cookson. “Mitochondrial Quality Control and Dynamics in Parkinson’s Disease.” Antioxidants & Redox Signaling 16, no. 9 (May 1, 2012): 869–882. doi:10.1089/ars.2011.4019. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3292751/.
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