Sirtuins in neurodegenerative diseases: an update on potential mechanisms

Abstract

Silent information regulator 2 proteins (sirtuins or SIRTs) are a group of deacetylases (or deacylases) whose activities are dependent on and regulated by nicotinamide adenine dinucleotide (NAD(+)). Compelling evidence supports that sirtuins play major roles in many aspects of physiology, especially in pathways related to aging - the predominant and unifying risk factor for neurodegenerative diseases. In this review, we highlight the molecular mechanisms underlying the protective effects of sirtuins in neurodegenerative diseases, focusing on protein homeostasis, neural plasticity, mitochondrial function, and sustained chronic inflammation. We will also examine the potential and challenges of targeting sirtuin pathways to block these pathogenic pathways.

Keywords: NF-κB; SIRT1; amyloid-β; epigenetic regulation; inflammation; mitochondria; neurodegeneration; tau.

FIGURE 1

Protective mechanisms of SIRT1 in AD. SIRT1 deacetylates tau protein at multiple residues, and enhances tau polyubiquitination and subsequent proteasomal degradation. Overexpression of SIRT1 deacetylates retinoic acid receptor (RAR) β and activates ADAM10, a component of the α-secretase, which processes APP along an anti-amyloidogenic pathway that decreases formation of toxic Aβ species. SIRT1 was also shown to enhance α-secretase cleavage via a mechanism involving reducing ROCK1, which suppresses α-secretase cleavage.

FIGURE 2

Anti-inflammatory mechanisms of SIRT1. SIRT1 deacetylates p65 and blocks the transactivation of NF-κB-dependent gene expression. SIRT1 suppresses the activity of PARP-1, a coactivator of NF-κB-dependent transcription, by deacetylation and by inhibiting its expression. PARP-1 activation could deplete NAD⁺, resulting in inhibition of SIRT1 and NF-κB activation. On the epigenetic level, SIRT1 represses NF-κB-dependent inflammatory gene expression by deacetylating H4K16 and also by recruiting more components of repressor complexes. SIRT1 deacetylates and activates histone methyltransferase SUV39H1, which suppresses expression of inducible inflammatory genes. DNA methylation is associated with suppressed expression. Whether SIRT1 could inhibit expression of inflammatory genes by enhancing promoter methylation remains to be determined.