SIRT-mediated deacetylation is an important epigenetic alteration.

The SIRT family comprises seven protein members (namely, SIRT1-7). While the catalytic core domain contains amino acid residues that have remained stable throughout the entire evolutionary process, the N- and C-terminal regions are structurally divergent and contribute to differences in subcellular localization, enzymatic activity and substrate specificity

SIRT1 and SIRT2 are localized in the nucleus and cytoplasm. SIRT3, SIRT4, and SIRT5 are mitochondrial, and SIRT6 and SIRT7 are predominantly found in the nucleus.

Sirtuins are a conserved family of nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylases and ADP-ribosyltransferases. SIRT1, located in the nucleus and cytoplasm, functions through deacetylation of its substrates that are regulators of metabolism and aging. Moderate overexpression or pharmaceutical activation of SIRT1 is usually associated with improved healthspan and/or lifespan in several organisms; therefore, strategies to stimulate SIRT1 catalytic activity are being pursued for aging intervention.

Role of SIRT1 in autoimmune demyelination and neurodegeneration

. It has gained a lot of attention recently because many studies in animal models of demyelinating and neurodegenerative diseases have shown that SIRT1 induction can ameliorate the course of the disease.

SIRT1 expression was found to be decreased in the peripheral blood mononuclear cells of MS patients during relapses. SIRT1 represents a possible biomarker of relapses and a potential new target for therapeutic intervention in MS. Modulation of SIRT1 may be a valuable strategy for treating or preventing MS and neurodegenerative central nervous system disorders.

SIRT1 inactivation switches reactive astrocytes to an antiinflammatory phenotype in CNS autoimmunity

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Figure 1. Inactivation of SIRT1 promotes antiinflammatory astrocytes.

(A and B) Primary astrocytes were isolated from naive newborn C57BL/6 mice at P2, treated with resveratrol (Resv) or DMSO for 24 hours, and then stimulated with cocktail (C1q, TNF, IL-1α) for another 24 hours. Expression of representative A1/A2 astrocyte markers (A) and proinflammatory cytokines (B) was determined by RT-PCR. n = 3 per group; 1-way ANOVA. (C–G) Primary astrocytes isolated from LSL-Cas9 mice (D) were infected with lentivirus carrying Cre with sgSirt1 or sgScram (C). Forty-eight hours after infection, cells were selected with puromycin for 3 days, and knockout efficiency was analyzed by Western blotting (E). sgSirt1- and sgScram-treated astrocytes were stimulated with the cocktail for 24 hours and assayed by immunostaining for their morphology (F), by microarray for the RNA expression profiles (G), and by RT-PCR to measure the expression of neurotoxic (“A1”), neuroprotective (“A2”), and pan-reactive astrocyte markers (8) (H), pro- or antiinflammatory molecules (I), and chemokines (J). n = 3 per group; unpaired, 2-tailed t test. All results are expressed as the mean ± SD. *P < 0.05 (a), **P < 0.01 (b), ***P < 0.001 (c), and ****P < 0.0001 (d). Data from 1 representative experiment of 3 are shown.

2024年8月4日 | カテゴリー：各種病因学, 膠原病, 免疫疾患 |

SIRT-mediated deacetylation is an important epigenetic alteration.

Role of SIRT1 in autoimmune demyelination and neurodegeneration

SIRT1 inactivation switches reactive astrocytes to an antiinflammatory phenotype in CNS autoimmunity

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