The Sirtuin 2 microtubule deacetylase is an abundant neuronal protein that accumulates in the aging CNS

Abstract

Sirtuin 2 (SIRT2) is one of seven known mammalian protein deacetylases homologous to the yeast master lifespan regulator Sir2. In recent years, the sirtuin protein deacetylases have emerged as candidate therapeutic targets for many human diseases, including metabolic and age-dependent neurological disorders. In non-neuronal cells, SIRT2 has been shown to function as a tubulin deacetylase and a key regulator of cell division and differentiation. However, the distribution and function of the SIRT2 microtubule (MT) deacetylase in differentiated, postmitotic neurons remain largely unknown. Here, we show abundant and preferential expression of specific isoforms of SIRT2 in the mammalian central nervous system and find that a previously uncharacterized form, SIRT2.3, exhibits age-dependent accumulation in the mouse brain and spinal cord. Further, our studies reveal that focal areas of endogenous SIRT2 expression correlate with reduced α-tubulin acetylation in primary mouse cortical neurons and suggest that the brain-enriched species of SIRT2 may function as the predominant MT deacetylases in mature neurons. Recent reports have demonstrated an association between impaired tubulin acetyltransferase activity and neurodegenerative disease; viewed in this light, our results showing age-dependent accumulation of the SIRT2 neuronal MT deacetylase in wild-type mice suggest a functional link between tubulin acetylation patterns and the aging brain.

NAD Biosynthesis in Humans - Enzymes, Metabolites and Therapeutic Aspects

“…In paper I, analysis of cDNA from several human cell lines revealed the existence of a new splice variant and confirmed the previously reported data from mice [143,144].…”

Increased expression of SIRT2 is a novel marker of cellular senescence and is dependent on wild type p53 status

“…SIRT2 mainly exists in 2 different isoforms [Isoform 1 (389 aa: 43 kDa) and isoform 2 (352 aa: 39 kDa)] and both these isoforms showed increased expression during senescence. 28 It has to be noted that SIRT2 antibody identified both the isoforms on the immunoblot with almost similar intensity. For quantification, the fold increase for both the isoforms were calculated and their average was taken as the total increase in SIRT2 pool which was approximately 3 fold higher in senescent cells compared to the control (Fig.…”

“…In mouse brain 3 different isoforms of SIRT2 have been detected, SIRT2.1, 2.2. and 2.3, of which the 2.3 isoform showed an increase with age in the central nervous system. 28 However, a recent report indicated that increase in SIRT2 levels in aged rat brain is specific only to occipital region and no other regions. 36 In contrast to the results of our study, a recent report by Kilic Eren et al, (2015) 37 showed decrease in SIRT2 levels in resveratrol induced premature senescence in human fibroblasts.…”

Defective recruitment of motor proteins to autophagic compartments contributes to autophagic failure in aging

“…In contrast, few studies have focused on the microtubule cytoskeleton of aging cells, except for the acetylation‐induced instability of neuronal microtubules in the context of dementia (Maxwell et al., 2011; Raes & Remacle, 1987; Schatten, Chakrabarti & Hedrick, 1999). Our microscopic evaluation did not reveal gross changes in the organization of tubulin and acetylated tubulin that could explain the observed changes in autophagic vesicular trafficking.…”