Sirtuins as pharmacological targets in neurodegenerative and neuropsychiatric disorders

Abstract

Histone deacetylases (HDACs) are enzymes that regulate several processes, such as transcription, cell proliferation, differentiation and development. HDACs are classified as either Zn 2+ -dependent or NAD + -dependent enzymes. Over the years, experimental and clinical evidence has demonstrated that HDAC modulation is a critical process in neurodegenerative and psychiatric disorders. Nevertheless, most of the studies have focused on the role of Zn 2+ -dependent HDACs in the development of these diseases, although there is growing evidence showing that the NAD + -dependent HDACs, known as sirtuins, are also very promising targets. This possibility has been strengthened by reports of decreased levels of NAD + in CNS disorders, which can lead to alterations in sirtuin activation and therefore result in increased pathology. In this review, we discuss the role of sirtuins in neurodegenerative and neuropsychiatric disorders as well the possible rationale for them to be considered as pharmacological targets in future therapeutic interventions.LINKED ARTICLES: This article is part of a themed issue on Building Bridges in Neuropharmacology. To view the other articles in this section visit http://onlinelibrary.

MicroRNA 132-3p Is Upregulated in Laron Syndrome Patients and Controls Longevity Gene Expression

“…SIRT1 is the most extensively studied member of the sirtuins, a family of mammalian class III histone deacetylases implicated in health span and longevity. SIRT1 has multiple physiological functions as well as wide-ranging roles in pathological settings [ 75 , 76 ]. SIRT1 is one of seven human sirtuins that possess mono-ADP-ribosyltransferase or deacetylase activity toward target proteins, including histones.…”

Sirtuin 1 in Host Defense during Infection

“…Nuclear SIRTs, including SIRT1, 2, 6, and 7, act as regulators of the inflammatory response [ 41 ]. Given the essential function of SIRTs in numerous biological pathways, their dysregulation and abnormal expression are, not surprisingly, associated with a variety of human diseases, including metabolic and neurodegenerative diseases, cardiovascular diseases, cancers, infection, and inflammatory diseases [ 42 , 43 , 44 , 45 ]. There is also a large body of evidence demonstrating a role for SIRTs in the epigenetic control of several target genes and proteins, by the modification of histone and non-histone proteins in both normal and transformed cells.…”

Building Bridges In Neuropharmacology: New therapeutic approaches for psychiatric and neurodegenerative disorders

“…Other pharmacological targets for neurodegeneration are less disease‐specific. One set of drug targets attracting particular interest are sirtuins, a family of NAD + ‐dependent histone deacetylases (Leite et al, 2022). These enzymes have roles in controlling key events in the cell nucleus, such as gene transcription and DNA repair, in modulating microtubule dynamics in the cytosol and in regulating cellular metabolism at mitochondria.…”

“…These enzymes have roles in controlling key events in the cell nucleus, such as gene transcription and DNA repair, in modulating microtubule dynamics in the cytosol and in regulating cellular metabolism at mitochondria. Agents that modulate the activity of sirtuins, most notably the antioxidant resveratrol, are believed to be therapeutically beneficial in a remarkable range of neurodegenerative and psychiatric disorders including Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, autism spectrum disorder (ASD), schizophrenia and bipolar disorder (Leite et al, 2022).…”