Targeting α -synuclein for treating Parkinson’s disease: mechanistic and therapeutic considerations

Summary Progressive neuronal cell loss in a small subset of brainstem and mesencephalic nuclei and widespread aggregation of the α -synuclein protein in the form of Lewy bodies and Lewy neurites are neuropathological hallmarks of Parkinson’s disease. Most cases occur sporadically, but mutations in several genes, including α -synuclein, are associated with disease development. The mechanisms driving neurodegeneration remain unknown, hence limiting therapeutic strategies aimed at blocking neuronal death. This review describes current evidence for a predominant role of α -synuclein in the pathogenesis of PD, as well as some of the most promising α -synuclein-based strategies currently in development for this incurable neurodegenerative disorder. progression and additional clinical features such as hallucinations, dementia, pyramidal tract impairment and autonomic failure 4, 10-12, 15 . Neuropathological reports on autopsies of PD patients with p.A53T, p.A30P, p.E46K and p.G51D mutations described dopaminergic cell loss with extensive synucleinopathy in several brain regions 10, 12, 16, 17 . The subsequent identification of families with duplication or triplication of the SNCA gene (PARK4 locus) strengthened the link between α -syn and PD, and indicated that increased levels of even the wild-type protein alone can cause the disease 18, 19 . The clinical phenotype of patients with SNCA triplication (i.e. early onset parkinsonism with dementia) is more severe than in those with SNCA duplication (i.e. close to idiopathic PD) suggesting a dose-dependent relationship between disease severity and SNCA gene dosage. The common genetic variability at the SNCA locus is a robust risk factor for disease. patent deposits. For the analysis, we used a collection of 3576 documents retrieved from Scopus for which we extracted citations count and compared to trends of press releases in large media by searching Factiva ® (Dow Jones) database. Two peaks emerge, a first in 2005 with the post-genomic revolution and the interference RNA technology breakthrough, and a second in 2010 the of the Michael J. Fox Foundation (MJFF) for candidate compounds and the launch of clinical trials (e.g. Affiris). in the of the biomarker clinical