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SIRT6 ROLES IN PROTECTING THE BRAIN FROM NEURODEGENERATION
Abstract
Aims
Aging is the main risk factor for developing a neurodegenerative disease. We have shown that the brain-specific SIRT6-deficient (brSIRT6-KO) mice presenting memory impairments, increased DNA damage, cell death, Tau stabilization, and more resembling AD diseases. Importantly AD patients have significantly less SIRT6 in their brains. SIRT6 influences gene expression by its roles in chromatin remodeling and affects different targets directly through PTMs. Our aim is to understand the molecular changes occurring in aging brains that lead to neurodegeneration.
Methods
bioinformatics, molecular biology, behavior, biochemistry
Results
Our results define four gene expression categories that change with age in a pathological or non-pathological manner, some of which Calorie Restriction can reverse. Importantly, each gene expression category is associated with specific transcription factors, thus serving as potential candidates for their category. In addition, we discovered that SIRT6 could regulate Tau migration to the nucleus through its deacetylation activity in residue K174. We discover that Tau hyper-acetylation at residue 174, a modification increasing in AD patients and enhance its stability, increases Tau’s nuclear presence in a DNA damage-dependent manner. However, lack of SIRT6 or DNA damage results in nuclear Tau-K174ac accumulation. Once there, it induces global changes in gene expression, affecting protein translation, and energy production. This phenomenon was also observed in AD patients.
Conclusions
Overall, SIRT6 has various critical roles in protecting the brain from neurodegeneration. This model is important as a new tool to understand sporadic age-related AD cases, representing 95% of the total cases. It will be key to finding novel targets and treatments for neurodegeneration.