Abstract
α-Synuclein is a small protein that has special relevance for understanding Parkinson disease and related disorders. Not only is α-synuclein found in Lewy bodies characteristic of Parkinson disease, but also mutations in the gene for α-synuclein can cause an inherited form of Parkinson disease and expression of normal α-synuclein can increase the risk of developing Parkinson disease in sporadic, or non-familial, cases. Both sporadic and familial Parkinson disease are characterized by substantial loss of several groups of neurons, including the dopaminergic cells of the substantia nigra that are the target of most current symptomatic therapies. Therefore, it is predicted that α-synuclein, especially in its mutant forms or under conditions where its expression levels are increased, is a toxic protein in the sense that it is associated with an increased rate of neuronal cell death. This review will discuss the experimental contexts in which α-synuclein has been demonstrated to be toxic. I will also outline what is known about the mechanisms by which α-synuclein triggers neuronal damage, and identify some of the current gaps in our knowledge about this subject. Finally, the therapeutic implications of toxicity of α-synuclein will be discussed.
Highlights
All neurodegenerative diseases share the common phenomenon that neurons, usually relatively specific groups, are lost progressively as the disease develops
Both sporadic and familial Parkinson disease are characterized by substantial loss of several groups of neurons, including the dopaminergic cells of the substantia nigra that are the target of most current symptomatic therapies
If we propose that insoluble fibrils are toxic, a 'fibril-buster' would be the way forward [reviewed in [111]], but if soluble oligomers damage cells we would want to prevent their formation or encourage their turnover
Summary
Cell death is a significant part of the pathology of PD. The process is a mysterious, the prime suspect for a toxic protein is α-synuclein. Assuming toxicity does result from aberrant forms of the protein, including increased expression of the normal gene, there are two major aspects that might be targeted therapeutically. The protein is prone to aggregate and anti-aggregative compounds, or approaches to limit net expression levels, may be helpful. There are a number of molecular events that largely revolve around membrane or organelle interactions that may contribute to toxicity, and these too may be targeted therapeutically. Future work should be directed at exploring these possibilities as http://www.molecularneurodegeneration.com/content/4/1/9 well as at developing models that have a stronger cell death signal, to more accurately represent the substantive loss of neurons seen in PD. DLB/DLBD: Dementia with Lewy bodies/Diffuse Lewy Body Disease; ER: endoplasmic reticulum; L-DOPA: 3,4dihydroxy-L-phenylalanine; PD: Parkinson disease
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