Dataset Information

The mechanistic target of rapamycin (mTOR) and the silent mating-type information regulation 2 homolog 1 (SIRT1): oversight for neurodegenerative disorders.

ABSTRACT: As a result of the advancing age of the global population and the progressive increase in lifespan, neurodegenerative disorders continue to increase in incidence throughout the world. New strategies for neurodegenerative disorders involve the novel pathways of the mechanistic target of rapamycin (mTOR) and the silent mating-type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) that can modulate pathways of apoptosis and autophagy. The pathways of mTOR and SIRT1 are closely integrated. mTOR forms the complexes mTOR Complex 1 and mTOR Complex 2 and can impact multiple neurodegenerative disorders that include Alzheimer's disease, Huntington's disease, and Parkinson's disease. SIRT1 can control stem cell proliferation, block neuronal injury through limiting programmed cell death, drive vascular cell survival, and control clinical disorders that include dementia and retinopathy. It is important to recognize that oversight of programmed cell death by mTOR and SIRT1 requires a fine degree of precision to prevent the progression of neurodegenerative disorders. Additional investigations and insights into these pathways should offer effective and safe treatments for neurodegenerative disorders.

SUBMITTER: Maiese K

PROVIDER: S-EPMC5906169 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The mechanistic target of rapamycin (mTOR) and the silent mating-type information regulation 2 homolog 1 (SIRT1): oversight for neurodegenerative disorders.

Maiese Kenneth K

Biochemical Society transactions 20180309 2

As a result of the advancing age of the global population and the progressive increase in lifespan, neurodegenerative disorders continue to increase in incidence throughout the world. New strategies for neurodegenerative disorders involve the novel pathways of the mechanistic target of rapamycin (mTOR) and the silent mating-type information regulation 2 homolog 1 (<i>Saccharomyces cerevisiae</i>) (SIRT1) that can modulate pathways of apoptosis and autophagy. The pathways of mTOR and SIRT1 are cl ...[more]

PMID: 29523769

Similar Datasets

Project description:BackgroundHypertension can lead to podocyte damage and subsequent apoptosis, eventually resulting in glomerulosclerosis. Although alleviating podocyte apoptosis has clinical significance for the treatment of hypertensive nephropathy, an effective therapeutic target has not yet been identified. The function of septin4, a proapoptotic protein and an important marker of organ damage, is regulated by post-translational modification. However, the exact role of septin4 in regulating podocyte apoptosis and its connection to hypertensive renal damage remains unclear.MethodsWe investigated the function and mechanism of septin4 in hypertensive nephropathy to discover a theoretical basis for targeted treatment. Mouse models including Rosa 26 (Gt(ROSA)26Sor)-SIRT2 (silent mating type information regulation 2 homolog-2)-Flag-TG (transgenic) (SIRT2-TG) mice SIRT2-knockout, and septin4-K174Q mutant mice, combined with proteomic and acetyl proteomics analysis, followed by multiple molecular biological methodologies, were used to demonstrate mechanisms of SIRT2-mediated deacetylation of septin4-K174 in hypertensive nephropathy.ResultsUsing transgenic septin4-K174Q mutant mice treated with the antioxidant Tempol, we found that hyperacetylation of the K174 site of septin4 exacerbates Ang II (angiotensin II)- induced hypertensive renal injury resulting from oxidative stress. Proteomics and Western blotting assays indicated that septin4-K174Q activates the cleaved-PARP1 (poly [ADP-ribose] polymerase family, member 1)-cleaved-caspase3 pathway. In septin4-knockdown human renal podocytes, septin4-K174R, which mimics deacetylation at K174, rescues podocyte apoptosis induced by Ang II. Immunoprecipitation and mass spectrometry analyses identified SIRT2 as a deacetylase that interacts with the septin4 GTPase domain and deacetylates septin4-K174. In Sirt2-deficient mice and SIRT2-knockdown renal podocytes, septin4-K174 remains hyperacetylated and exacerbates hypertensive renal injury. By contrast, in Rosa26-Sirt2-Flag (SIRT2-TG) mice and SIRT2-knockdown renal podocytes reexpressing wild-type SIRT2, septin4-K174 is hypoacetylated and mitigates hypertensive renal injury.ConclusionsSeptin4, when activated through acetylation of K174 (K174Q), promotes hypertensive renal injury. Septin4-K174R, which mimics deacetylation by SIRT2, inhibits the cleaved-PARP1-cleaved-caspase3 pathway. Septin4-K174R acts as a renal protective factor, mitigating Ang II-induced hypertensive renal injury. These findings indicate that septin4-K174 is a potential therapeutic target for the treatment of hypertensive renal injury.

Project description:IntroductionIntervertebral disc tissue homeostasis is modulated by a variety of molecules. Silent mating type information regulator 2 homolog 1 (SIRT1) plays a key role in various physiological processes. The aim of the present study was to verify the expression of SIRT1 and determine SIRT1 function in human intervertebral disc cell homeostasis.MethodsHuman nucleus pulposus (NP) cells were obtained from 24 surgical patients (mean age: 39.4 years) and monolayer-cultured. SIRT1 expression was investigated using RT-PCR analysis and immunohistochemical staining. Quantitative real-time RT-PCR was performed to detect mRNA expression of SIRT1 and other genes: aggrecan, collagen type 2 and Sox9. The effect of SIRT1 on the extracellular matrix metabolism of NP cells was examined using recombinant human SIRT1 protein and a protein delivery reagent. Cell number and proliferation activity were measured following SIRT1 treatment. To reveal the deacetylation potential of transfected recombinant human SIRT1, western blotting for acetylated p53 was utilized. R-phycoerythrin was used for the negative control.ResultsSIRT1 expression was confirmed at both mRNA and protein levels in almost all NP cells. Real-time RT-PCR analysis showed SIRT1 mRNA expression significantly increased with donor age (P <0.05, ρ = 0.492). Pfirrmann grade 3 discs showed significantly higher SIRT1 mRNA expression than other grades. SIRT1 treatment significantly reduced aggrecan, Sox9 and collagen type 2 mRNA expression in a dose-dependent manner in all disease classes and disc degeneration grades. Proliferation activity was decreased by SIRT1 treatment in lumbar spinal stenosis and lumbar disc herniation, Pfirrmann grade 3 and grade 4 discs. In contrast, it was significantly upregulated in idiopathic scoliosis, Pfirrmann grade 2 discs. The negative control protein did not affect extracellular matrix metabolism or proliferation activity.ConclusionsWe demonstrate for the first time that SIRT1 is expressed by human NP cells. SIRT1 expression was significantly elevated in an early degeneration stage. SIRT1 affected both extracellular matrix metabolism and proliferation activity; the effect of SIRT1 was altered according to disease class and disc degeneration grade. SIRT1 appears to play a key role in homeostasis during the human intervertebral disc degeneration process.

Dataset Information

The mechanistic target of rapamycin (mTOR) and the silent mating-type information regulation 2 homolog 1 (SIRT1): oversight for neurodegenerative disorders.

Publications

The mechanistic target of rapamycin (mTOR) and the silent mating-type information regulation 2 homolog 1 (SIRT1): oversight for neurodegenerative disorders.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets