Sirt1’s beneficial roles in neurodegenerative diseases – a chaperonin containing TCP‐1 (CCT) connection?

Abstract

Sir2 ⁄ Sirt1 and its orthologues are known lifespan extension factors in several aging models from yeast to invertebrates. Sirt1 activation is also known to be beneficial and protective in both invertebrate and mammalian models of neurodegenerative disease. Sirt1’s lifespan extension effect, as well as the beneficial outcome of its activation in models of aging-associated diseases, is often attributed to its ability to instill a gene expression profile that is pro-survival and antiaging. A recent report from Nyström and colleagues showed that the yeast Sir2p affects the function of the polarisome in segregation and retrograde transport of damaged and aggregated proteins from the bud to the mother cell, thereby ensuring the generation of a 'rejuvenated' daughter cell. Interestingly, the role of Sir2p in this case involves deacetylation and activation of cytoplasmic chaperonin containing TCP-1 (CCT, or TriC), thereby enhancing actin folding and polymerization. In view of a previously documented role of CCT in modulating polyglutamine-containing protein aggregation and toxicity, we hypothesized that CCT deacetylation may also underlie Sirt1’s beneficial effects in several neurodegenerative diseases precipitated by toxic aggregates. Other than alterations in gene expression profile, another major way whereby Sirt1 activation may counter neural aging could be to promote neuronal survival via prevention of toxic aggregate formation through CCT.