The Role of SIRT3 in the Brain Under Physiological and Pathological Conditions.

Elena Sidorova-Darmos,James H Eubanks,Rosa Sommer

doi:10.3389/fncel.2018.00196

Elena Sidorova-Darmos, James H Eubanks + Show 1 more

Open Access

https://doi.org/10.3389/fncel.2018.00196

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Abstract

Sirtuin enzymes are a family of highly seven conserved protein deacetylases, namely SIRT1 through SIRT7, whose enzymatic activities require the cofactor nicotinamide adenine dinucleotide (NAD+). Sirtuins reside in different compartments within cells, and their activities have been shown to regulate a number of cellular pathways involved in but not limited to stress management, apoptosis and inflammatory responses. Given the importance of mitochondrial functional state in neurodegenerative conditions, the mitochondrial SIRT3 sirtuin, which is the primary deacetylase within mitochondria, has garnered considerable recent attention. It is now clear that SIRT3 plays a major role in regulating a host of mitochondrial molecular cascades that can contribute to both normal and pathophysiological processes. However, most of the currently available knowledge on SIRT3 stems from studies in non-neuronal cells, and the consequences of the interactions between SIRT3 and its targets in the CNS are only beginning to be elucidated. In this review, we will summarize current advances relating to SIRT3, and explore how its known functions could influence brain physiology.

Highlights

It has been over three decades since the silent information regulator 2 (Sir2) gene was initially identified in yeast (Shore et al, 1984; Ivy et al, 1986; Rine and Herskowitz, 1987; Tanner et al, 2000) and its product shown to regulate DNA recombination/repair, gene silencing and chromosomal stability (Brachmann et al, 1995; Kaeberlein et al, 1999)
SNc dopaminergic neuron degeneration was prevented by either reintroduction of functional SIRT3, or by introduction of a constitutively active deacetylation-mimetic form of MnSODK68 (Shi et al, 2017). These studies suggest that the endogenous functions of SIRT3 may play a protective role in Parkinsonism disease (PD) pathogenesis, and suggest SIRT3 may represent a therapeutic target for PD translational development, since hyperacetylation of MnSODK68 has been observed in post-mortem midbrain tissues from PD patients (Shi et al, 2017)
Current research sheds light on the widespread role that SIRT3 activity may play in regulating normal brain function, and how its activities could influence the pathogenic course of stroke and different neurodegenerative diseases

Summary

Introduction

It has been over three decades since the silent information regulator 2 (Sir2) gene was initially identified in yeast (Shore et al, 1984; Ivy et al, 1986; Rine and Herskowitz, 1987; Tanner et al, 2000) and its product shown to regulate DNA recombination/repair, gene silencing and chromosomal stability (Brachmann et al, 1995; Kaeberlein et al, 1999). While there have been fewer studies of SIRT3 activity in neural cells or tissues, studies employing non-neuronal systems have uncovered a number of mitochondrial proteins targeted by SIRT3 that are expressed in brain, and it seems likely they will be targeted by SIRT3 in nervous system settings.

Results

Conclusion