Will Sirtuin 2 Be a Promising Target for Neuroinflammatory Disorders?

Abstract

Neuroinflammatory disorder is a general term that is associated with the progressive loss of neuronal structure or function. At present, the widely studied diseases with neuroinflammatory components are mainly divided into neurodegenerative and neuropsychiatric diseases, namely, Alzheimer's disease, Parkinson's disease, depression, stroke, and so on. An appropriate neuroinflammatory response can promote brain homeostasis, while excessive neuroinflammation can inhibit neuronal regeneration and damage the central nervous system. Apart from the symptomatic treatment with cholinesterase inhibitors, antidepressants/anxiolytics, and neuroprotective drugs, the treatment of neuroinflammation is a promising therapeutic method. Sirtuins are a host of class III histone deacetylases, that require nicotinamide adenine dinucleotide for their lysine residue deacetylase activity. The role of sirtuin 2 (SIRT2), one of the sirtuins, in modulating senescence, myelin formation, autophagy, and inflammation has been widely studied. SIRT2 is associated with many neuroinflammatory disorders considering it has deacetylation properties, that regulate the entire immune homeostasis. The aim of this review was to summarize the latest progress in regulating the effects of SIRT2 on immune homeostasis in neuroinflammatory disorders. The overall structure and catalytic properties of SIRT2, the selective inhibitors of SIRT2, the relationship between immune homeostasis and SIRT2, and the multitasking role of SIRT2 in several diseases with neuroinflammatory components were discussed.

Keywords: deacetylation; inflammatory; neuroinflammatory disorders; neuroprotection; promising target; sirtuin 2 (SIRT2).

FIGURE 1

Subcellular location of 7 mammalian SIRTs (SIRT1–7) and SIRT2 related to neuroinflammatory disorders. SIRT1, SIRT6, and SIRT7 were found in the nucleus of the cell. Under certain conditions, SIRT1 can be transported from the nucleus to the cytoplasm. SIRT6 was also found in heterochromatin and the endoplasmic reticulum. SIRT7 was located at the nucleolus. SIRT3, SIRT4, and SIRT5 were found in the mitochondria and contribute to oxidative stress alleviation by regulating the activity of specific metabolic enzymes. SIRT3 is moved between the nucleus and mitochondria under cellular stress. The main site of SIRT2 was the cytoplasm, but in some phases of the cell cycle it was also found in the nucleus. SIRT2 was involved in the pathogenesis and progression of neuroinflammatory disorders.

FIGURE 2

The overall structure of SIRT2. (A) Synthesis of SIRT2 inhibitors. (B) Schematic representation of human SIRT2. The conserved large catalytic domain was shown in gray. Numbers referred to amino acid residues in the proteins. (C) SIRT2 consisted of two domains that were connected by several conserved loops. (D) The SIRT2 enzymatic reaction was composed of three sequential steps, two of which were reversible and the final one irreversible.

FIGURE 3

The known SIRT2-selective inhibitors (A) and its name of the compound (B).

FIGURE 4

Schematic diagram of the interactions of distinct cell types in four diseases.