Research ArticleHuntington’s Disease

Targeting ATM ameliorates mutant Huntingtin toxicity in cell and animal models of Huntington’s disease

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Science Translational Medicine  24 Dec 2014:
Vol. 6, Issue 268, pp. 268ra178
DOI: 10.1126/scitranslmed.3010523

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Cashing in with ATM

Age-related neurodegenerative disorders, including Alzheimer’s disease and Huntington’s disease (HD), consistently show elevated markers of DNA damage. It remains unclear, however, whether such defects are mere consequences of or actively contribute to disease processes. In a new study, Lu et al. show that ataxia-telangiectasia mutated (ATM), a pivotal signaling molecule in the DNA damage response pathway, can modify the toxicity of the mutant protein that causes HD. ATM signaling activity was aberrantly increased in HD cells, animal models of HD, and postmortem brain tissue from HD patients. Reducing ATM signaling by genetic manipulation or using small-molecule inhibitors of ATM consistently reduced HD protein toxicities in cellular and animal models.