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

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

## Braak Staging theory

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. (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), the hypothesis is now accepted as a largely valid account 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

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(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 and Alzheimer's also involve alpha-synuclein pathology. Why the aggregation in such diseases affects different cell types awaits an answer.

## Propensity to aggregate

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.
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.
* modification by oxidation, nitration and phosphorylation
* inflammation
       Inflammation and aggregation of α-syn are dynamically interlinked
* genetic variation
The review by Stefanis (2012), “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. See also Fig 3 opposite.

## Pro-inflammatory nature of abnormal alpha-synuclein

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

(Not necessarily in this order)
Progression through nervous system - prion-like behaviour
The toxic species
Oxidation, nitrosation and phosphorylation
The 'normal' role of a-syn
The 'normal' conformation of the protein
Variations in SNCA gene
Inflammation and the immune response
Alternative splicing
UPS and autophagy
Relationship to mitochondrial dysfunction
Treatment strategies, pros and cons