SIRT6 deficiency may contribute to neurodegeneration

Aging is considered a result of DNA damage accumulation. Both normal metabolic activities and environmental factors can cause DNA damage in human cells. Human cells employ multiple DNA repair mechanisms to monitor and repair damaged DNA. When these repair mechanisms fail to work, unrepaired DNA damages may accumulate in the cell and impair its normal function.

The accumulation of DNA damage is particularly dangerous in the brain. There is evidence that DNA damage accumulation is even higher in the brains of patients with neurodegenerative disorders like Alzheimer's disease (AD). But the underlying mechanism remains unclear.

Now, a new study appearing in Cell Reports uncovers that a protein called SIRT6 is a key component of the DNA repair process. The study, conducted by researchers from the Ben-Gurion University of the Negev in Israel, Harvard Medical School in the USA, and the University of Leipzig in Germany, demonstrates that high SIRT6 levels promote DNA repair whereas low SIRT6 levels enable DNA damage accumulation.

SIRT6 belongs to the Sirtuin protein family, which has been linked with many cellular processes, such as aging, transcription, glycolysis, apoptosis, and inflammation. Mammals possess seven sirtuins (SIRT1-7). Lack of SIRT6 leads to genomic instability, premature aging, and death in mice. In contrast, mice that produce more SIRT6 protein exhibits an extended maximum lifespan. Aging rats have decreased levels of SIRT6 in their brains. At the molecular level, SIRT6 recruits molecules critical for proper DNA repair to the DNA damage sites. Cells lacking SIRT6 fail to repair DNA damage.

To determine the relationship between SIRT6, DNA damage accumulation, and neurodegeneration, the researchers created a brain-specific SIRT6-knockout mouse model. The brains of the mice exhibited pathological marks associated with DNA damage and neurodegeneration, and the mice developed behavioral defects. Additionally, cells lacking SIRT6 were more sensitive to genotoxic insults.

Next, the researchers measured the levels of SIRT6 in sporadic AD brain samples and analyzed normal brain gene expression. Results showed that the protein is highly expressed in normal human brains but is significantly decreased in AD patients.

Collectively, the study suggests that SIRT6 protects the brain from DNA damage accumulation and neurodegeneration. So targeting SIRT6 or its downstream signaling could be a potential therapeutic strategy for AD and age-related neurodegeneration.
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