Sirtuin 2 inhibitor, neuronal cell death and alpha synuclein
 

Possible Parkinson’s Lead

Several neurodegenerative disorders associated with protein misfolding are also intimately tied into aging. Biological pathways involved in aging may thus provide targets for therapeutic intervention in these diseases. In a Report in the 27 Jul 2007 Science Outeiro et al. identified a compound that can modulate the toxicity and aggregation of alpha-synuclein, a protein associated with Parkinson’s disease. The compound selectively inhibits the activity of sirtuin 2 (SIRT2), one of a family of proteins called histone deacetylases that participate in a variety of cellular functions and play a role in aging. The inhibitor protected neuronal cells against cell death both in vitro and in a fly model of Parkinson’s disease.

Genetic inhibition of SIRT2 by RNA interference similarly protected against alpha-synuclein toxicity. Interestingly, the SIRT2 inhibitor increased the size of alpha-synuclein aggregrates in a cellular model of the disease, an effect that might help reduce aberrant interactions of aggregates with cellular proteins. As noted in an accompanying Perspective by A. Dillin and J. W. Kelly, "[t]he study not only identifies SIRT2 as a potential new target for Parkinson’s disease intervention, but also bolsters recent work linking age-related cell signaling pathways to protein aggregation processes and age-onset neurodegenerative diseases."