a-Synuclein (aS) is a small (i.e., 140 amino acids) protein predominantly expressed in neurons and concentrated in presynaptic terminals. Although the function(s) of aS is still ill defined, evidence suggests a potential role in neural plasticity and regulation of synaptic vesicle pool. The deposition of aS as fibrillary proteinaceous aggregates in the cytoplasm of neurons or glial cells is the hallmark lesion in a group of neurodegenerative diseases including Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA) and its various subtypes MSA-P and MSA-C, neurodegeneration with brain iron accumulation type 1 (NBIA1; formerly known as Hallerworden-Spatz disease) and pure autonomic failure. For this reason all these disorders are now collectively referred to as synucleinopathies.
Fibrillary aS is the main component of Lewy bodies, pale bodies and Lewy neurites which are mainly concentrated in brainstem nuclei in PD and are more widely distributed throughout paralimbic and neocortical regions in DLB. A different aspect of aS deposition is found in MSA where aS fibrils mainly form glial cytoplasmic inclusions which typically develop in oligodendrocytes.
The molecular mechanisms responsible for neuronal and glial attrition in PD and related synucleinopathies are poorly understood. However, the identification of aS protein as the main component of hallmark lesions and the discovery that point mutations in the aS gene can be pathogenic in rare pedigree of familial PD with early onset strongly implicates aS in the pathogenesis of PD and other synucleinopathies. However, most PD cases are sporadic implicating that some post-translational modifications must underlie the aggregation of aS. Thus it has been recently shown that residue Ser 129 of aS is extensively phosphorylated in synucleinopathy lesions and that phosphorylation of aS at Ser129 promotes the formation of aS under in vitro conditions. In vitro studies have also shown that aS may interact with ubiquitin-proteasomal processing and that an excess of aS may be toxic to cells for instance by interacting with oxidative stress or mitochondrial function.
A number of transgenic mice models overexpressing human mutated or wild type aS have been developed and viral vector for targeting human aS trangene expression has been recently introduced to obtain high local aS expression in murine central nervous system. Although none of these models accurately reproduce PD features many of them exhibit significant aS-associated neurodegeneration and thus represent powerful and promising tools to investigate neurotoxicity of overexpressed aS.
In this presentation we will shortly review the molecular properties of aS, the different diseases characterized by the accumulation of aS and the recent contributions of animals models of PD.
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