Sirtuins as a link between ageing and neurodegeneration

Parkinson's disease (PD) affects millions of lives, yet the molecular mechanisms underlying neurodegeneration are poorly understood. Alpha-synuclein (alpha-syn), one of the proteins associated with PD, is the major component of Lewy body inclusions (LB). Overexpression of alpha-syn in cultured cells recapitulates central aspects of PD resulting from allele multiplication of the alpha-syn locus. We previously discovered a small molecule that rescues alpha-syn toxicity and modifies aggregation in vitro. We identified sirtuin 2 (SIRT2), a deacetylase enzyme of the class III of the histone deacetylase (HDAC) family, as a target for the inhibitor. The goal of this study was to develop and validate genetic tools for sirtuin inhibition. We employed a lentiviral system to express shRNA constructs for the knock-down of SIRT1, SIRT2 and SIRT3 in a mouse mesencephalic MES 23.5 cell line. Sirtuins expression levels were significantly decreased in cells infected with lentiviruses encoding for sirtuin-specific shRNA. Here we also show that silencing of SIRT2 leads to increased levels of acetylated alpha-tubulin. Altogether, our results implicate SIRT2 as a potentially important target for the development of small molecule inhibitors, in modifying the process of neurodegeneration in PD, opening novel avenues for therapeutic intervention.