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SIRT1, a NAD+-dependent deacetylase, protects neurons in a variety of in vitro and in vivo models of neurodegenerative disease. We have previously described a neuroprotective effect by SIRT1 independent of its catalytic activity. To confirm this conclusion we tested a panel of SIRT1 deletion mutant constructs, designated Δ1-Δ10, in cerebellar granule neurons induced to undergo apoptosis by low potassium treatment. We find that deletions of its N-terminal, those lacking portions of the catalytic domain, as well as one that lacks the ESA (Essential for SIRT1 Activity) motif, are as protective as wild-type SIRT1. In contrast, deletion of the region spanning residues 542-609, construct Δ8, substantially reduced the neuroprotective activity of SIRT1. As observed with LK-induced apoptosis, all SIRT1 constructs except Δ8 protect neurons against mutant huntingtin toxicity. Although its own catalytic activity is not required, neuroprotection by SIRT1 is abolished by inhibitors of Class I HDACs as well as by knockdown of endogenous HDAC1. We find that SIRT1 interacts with HDAC1 and this interaction is greatly increased by deleting regions of SIRT1 necessary for its catalytic activity. However, SIRT1-mediated protection is not dependent on HDAC1 deacetylase activity. Although other studies have described that catalytic activity of SIRT1 mediates is neuroprotective effect, our study suggests that in cerebellar granule neurons its deacetylase activity is not important and that HDAC1 contributes to the neuroprotective effect of SIRT1.
This article was published in the following journal.
Name: PloS one
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A catalytic subunit of the NuA4 histone acetyltransferase complex that functions in transcriptional activation of genes by acetylation of nucleosomal HISTONES H4 and H2A, altering nucleosome-DNA interactions and interaction of the modified histones with other activating transcription factors. It may control gene expression changes associated with oncogene and proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest; CELL AGING; APOPTOSIS; and DNA REPAIR. It is polyubiquitinated and degraded during HIV-1 infection through its interaction with the viral TAT PROTEIN.
RNA that has catalytic activity. The catalytic RNA sequence folds to form a complex surface that can function as an enzyme in reactions with itself and other molecules. It may function even in the absence of protein. There are numerous examples of RNA species that are acted upon by catalytic RNA, however the scope of this enzyme class is not limited to a particular type of substrate.
Biological molecules that possess catalytic activity. They may occur naturally or be synthetically created. Enzymes are usually proteins, however CATALYTIC RNA and CATALYTIC DNA molecules have also been identified.
Cell surface receptors for obesity factor (LEPTIN), a hormone secreted by the WHITE ADIPOCYTES. Upon leptin-receptor interaction, the signal is mediated through the JAK2/STAT3 pathway to regulate food intake, energy balance and fat storage.
A synuclein that is a major component of LEWY BODIES that plays a role in neurodegeneration and neuroprotection.