DNA repair in neurodegeneration

Genomic instability in mouse models of neurodegeneration, as seen in Alzheimer’s disease and ALS, is can be repaired by activating Sirtuin 1 (SIRT1), an enzyme that repairs damaged DNA, reports a study published online this week in Nature Neuroscience. These results demonstrate that there may be a therapeutic potential for SIRT1 activating drugs to possibly mitigate cellular damages associated with neurodegenerative diseases.

Unlike other cells in our bodies, neurons in the mammalian adult brain do not divide. DNA damage and the resulting genomic instability are therefore especially problematic for neurons since the defects cannot be repaired by making copies of the existing DNA. Moreover, physical breaks of DNA strands are associated with cognitive decline in aging humans and in neurodegenerative conditions, such as in Alzheimer’s disease and Lou Gehrig’s disease.

Because Sirtuins are enzymes known to protect the brain from cell death, Li-Huei Tsai and colleagues examined the molecular mechanism of their action. The authors found that without SIRT1, neurons cannot repair DNA damage induced by toxic chemicals. They also show that SIRT1 action is mediated by its regulation of a second enzyme that processes DNA packaging into a condensed form. The study also shows that treatment of mouse models of neurodegeneration and Alzheimer’s disease with a SIRT1 activator drug can also protect neurons against DNA damage.