SIRT1 and SIRT2 Activity Control in Neurodegenerative Diseases

Abstract

Sirtuins are NAD⁺ dependent histone deacetylases (HDAC) that play a pivotal role in neuroprotection and cellular senescence. SIRT1-7 are different homologs from sirtuins. They play a prominent role in many aspects of physiology and regulate crucial proteins. Modulation of sirtuins can thus be utilized as a therapeutic target for metabolic disorders. Neurological diseases have distinct clinical manifestations but are mainly age-associated and due to loss of protein homeostasis. Sirtuins mediate several life extension pathways and brain functions that may allow therapeutic intervention for age-related diseases. There is compelling evidence to support the fact that SIRT1 and SIRT2 are shuttled between the nucleus and cytoplasm and perform context-dependent functions in neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). In this review, we highlight the regulation of SIRT1 and SIRT2 in various neurological diseases. This study explores the various modulators that regulate the activity of SIRT1 and SIRT2, which may further assist in the treatment of neurodegenerative disease. Moreover, we analyze the structure and function of various small molecules that have potential significance in modulating sirtuins, as well as the technologies that advance the targeted therapy of neurodegenerative disease.

Keywords: SIRT1; SIRT2; modulators; neurodegenerative diseases; neuroprotective mechanism; resveratrol; selective pockets, sir reals.

FIGURE 1

Sirtuin family in cellular functions by targeting histone and non-histone proteins. All the isoforms of sirtuins can deacetylate substrates using NAD⁺ as a cofactor, which is released as nicotinamide, a by-product during the reaction. Sirtuins are mainly involved in cell senescence, DNA repair, cell survival and metabolism.

FIGURE 2

SIRT1 and SIRT2 activity in Alzheimer’s disease. (A) The deacetylation of tau protein by SIRT1 directs it to ubiquitination hence reduces neurofibrillary tangles (NFT). SIRT1 inhibition leads to the hyperphosphorylation of tau through increased activity of ApoE4 and OGT (B) The α-secretase activity increases with both the expression of ADAM10 and inhibition of deacetylated PARP1. (C) SIRT2 targets α-tubulin and Insulin/TGF-1 by deacetylation for neuronal protection.

FIGURE 3

SIRT1 and SIRT2 activities in Parkinson’s disease. Both SIRT1 and SIRT2 act independently on cell death in Parkinson’s diseases. SIRT1 downregulates c-PARP and NF-κβ and reduces the protein aggregation in cells (Top). SIRT2 acts on FOXO3a to translate SOD2, which reduces the ROS in the cells (Bottom). The FOXO3a deacetylation also expresses pro-apoptotic Bim. SIRT2 can surge the protein aggregation through deacetylation of α-Syn and α-tubulin. The deacetylation of cytoplasmic p53 inhibits autophagy and can enhance the PD pathology.

FIGURE 4

SIRT1 and SIRT2 in Huntington’s disease. Mutant huntington protein directly inhibits SIRT1 activity, affecting multiple pathways. In one of this pathway deacetylated TORC1 interacts with CREB, which is linked to DARPP32 and BDNF expression in neurons. Due to mutated HTT, the deacetylation of targets such as, TORC1, p53, FOXO3A, and PGC-1α will be inhibited that leads to cell death. Sterol biosynthesis also gets affected due to mutant. Inhibitors of SIRT2 found to decrease neurodegeneration in HD by the negative regulation of cholesterol biosynthesis.

FIGURE 5

The tertiary structure of SIRT1. (A) Schematic representation of SIRT1 domain structure. (B) Crystal structure of HDAC domain with (PDB: 4ZZI) and without (PDB: 4I5I) extended NTD. (C) The catalytic sites (A—C) of HDAC domain. SBD-STAC binding domain: HDAC, Histone deacetylase: CTR, C-terminal regulatory segment.

FIGURE 6

Deacetylation mechanism catalyzed by sirtuins. The cofactor NAD⁺ interacts with acyl lysine substrates to form an intermediate (not shown here) and releases the nicotinamide as a by-product. Further with the help of conserved catalytic His residue, sirtuin decomposes the intermediate to generate deacetylated lysine and the 2′-O-acyl ADPR (OAADPR).

FIGURE 7

Complexes of sirtuins with the inhibiting and activating compounds (STACs). (A) Alignment of the two crystal structures of SIRT1-STAC complexes (PDB: 5BTR, 4ZZI). (B) Position of various inhibitors on HDAC domain. (C) The hydrophobic binding surface of SBD. (D). The selectivity pocket (green) of SIRT2-HDAC domain responsible for the specific interactions of inhibitors.

FIGURE 8

Complex structures of sirtuins with different inhibitors. The interaction of selective and non‐selective sirtuin inhibitors bound to the respective isoforms has been compared to understand the significance of specific residues. (A) Non‐specific inhibitor, suramin binds to substrate and cofactor binding sites. (B) Indole molecule Ex‐243 specifically binds to the SIRT1 HDAC domain. (C) The inhibitors with thieno [3,2‐d] pyrimidine‐6‐carboxamide scaffold specifically affects SIRT1 activity at the catalytic site. (D‐F) SIRT2 specific inhibitors bind to the selectivity pocket. (G) The only inhibitor that binds away from the catalytic core is Halistanol sulfate. Black, hydrogen bond; Blue, water‐mediated interaction; Pink, π– stacking.