SIRT6 Enzyme Prevents Protein Waste Linked to Neurodegeneration

New research from Ben-Gurion University of the Negev has found a critical role for the SIRT6 enzyme in preventing the formation of protein waste. SIRT6 is a naturally produced enzyme, but it tends to decline over time. Prof. Debra Toiber’s research has shown that reduced SIRT6 levels play a critical role in aging and age-related neurodegeneration across multiple levels.

Prof. Toiber, her post-doctoral student Daniel Stein, her team and international collaborators found that SIRT6 is essential for maintaining protein homeostasis – namely, the regulation of the protein life cycle. Their findings were just published in Aging Cell.

Previous research has shown that in neurodegenerative diseases, such as Alzheimer's, Parkinson’s, ALS, and Huntington's, proteins misfold and form “aggregates”, which are protein junk that the cell cannot properly get rid of. In familial (genetic) cases of these diseases, the proteins are mutated, and that leads to their improper folding, but in 95% of neurodegenerative cases, the sporadic misfolding and aggregation remain unexplained. Stein and his colleagues discovered that SIRT6 prevents the formation of too many proteins (by preventing excessive rRNA formation and keeping the nucleolus tightly regulated), allowing the ones that are formed to properly pass quality control. When SIRT6 is not present, the cells do not limit themselves, generating too many proteins that, in the end, become toxic due to improper folding.

Importantly, when the group “paused” the excessive protein production with the FDA-approved drug 4PBA, they could reverse the protein folding stress and subsequently alleviate the neurodegenerative consequences of protein aggregates. In the model organism C.elegans, this drug increased the longevity and mobility of the defective worms, supporting the hypothesis that part of their problem was excessive protein production.

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