New Mechanism May Slow Huntington’s Disease

A new study from the Gray Faculty of Medical and Health Sciences at Tel Aviv University, conducted in collaboration with the Buck Institute for Research on Aging in California, has identified a promising therapeutic target for Huntington’s disease, a severe inherited neurodegenerative disorder for which no cure currently exists.

The study, led by Prof. Avraham Ashkenazi, PhD candidate Hasan Ishtayeh, and Prof. Lisa Ellerby, found that inhibiting the enzyme UCHL3 activates cellular “clean-up” mechanisms in neurons, reduces the accumulation of toxic proteins, and alleviates key pathological features of the disease.

Using advanced experimental models, including mouse neurons, cells derived from Huntington’s disease patients, and human stem cell-derived neurons, the researchers demonstrated that reducing UCHL3 activity enhances autophagy, the cell’s natural self-cleaning process. The intervention also activated the protective protein STAT3 and improved the condition of neurons that are particularly vulnerable in Huntington’s disease.

The team further discovered that a small-molecule UCHL3 inhibitor, originally developed for cancer research, reproduced these beneficial effects. The finding highlights the potential for repurposing drugs developed for one disease area to treat neurodegenerative disorders.

The study was published in Brain and reveals an unexpected biological connection between cancer and neurodegeneration. The findings may open new avenues for the development of innovative therapies not only for Huntington’s disease, but also for other neurodegenerative conditions, including Parkinson’s disease, Alzheimer’s disease, and ALS.

Read the paper:
https://doi.org/10.1093/brain/awag028