Towards a new therapeutic approach for Huntington's disease

Cholesterol is fundamental to the proper functioning of the various cell types in the brain, — including learning and memory — and its metabolism is deregulated in several neurodegenerative diseases.

In Huntington's disease, a neurodegenerative disease of genetic origin, many cellular dysfunctions are observed, leading to progressive degeneration and behavioral disorders. Deregulation of cholesterol metabolism, with a decrease in its synthesis pathway, but also increased degradation, was described in the literature. The team had previously shown that the enzyme CYP46A1, responsible for cholesterol catabolism, was deficient in patients, and mouse models of this disease.

The new study shows that the restoration of the enzyme CYP46A1 by gene therapy in a mouse model produces a global restoration of cholesterol metabolism, associated with a restoration of many cellular and molecular dysfunctions associated with the disease. Overall, this neuroprotection restores normal motor functions.

This study highlights the importance of metabolism restoration in therapeutic strategies for treating neurodegenerative diseases (Huntington's disease or Alzheimer's disease).

This article was the subject of an article in the CNRS letterand a short note on the INSB website.

CYP46A1 gene therapy deciphers the role of brain cholesterol metabolism in Huntington’s disease, R. Kacher, A. Lamazière, N. Heck, V. Kappes, C. Mounier, G. Despres, Y. Dembitskaya, E. Perrin, W. Christaller, S. Sasidharan Nair, V. Messent, N. Cartier, P. Vanhoutte, L. Venance, F. Saudou, C. Néri, J. Caboche, S. Betuing, Brain, awz174, 9 July 2019,


From team Neuronal Signaling and Gene Regulation, Neuroscience department Paris-Seine