A novel gene therapy-based approach with therapeutic potential in SCA3

Written by Dr. Ramya Lakshminarayan Edited by Dr. Judit M. Perez Ortiz

Cholesterol to the rescue: An alternative approach to treating SCA type 3 using gene therapy.

Spinocerebellar ataxia type 3 (SCA3) is a movement disorder that is caused by genetic mutations in a protein named Ataxin-3. Neurons in the cerebellum, striatum, and substantia nigra are important for movement, and these are affected in SCA3.

The mutant form of Ataxin-3 builds up in these neurons, eventually causing neurodegeneration and neuronal loss. The abnormal accumulation of mutant Ataxin-3 is in part due to impaired protein clearance, which is a hallmark of many other neurodegenerative diseases. Degradation (breaking down) and clearance (getting rid of) of protein aggregates are therefore crucial in the pathophysiology of neurodegeneration.

The balance between protein synthesis (creation) and degradation (destruction) is critical to the health of neurons. One of the ways in which neurons degrade proteins is called autophagy. This process is mediated by organelles called lysosomes in cells. Lysosomes employ digestive proteins to break down complex protein aggregates into simpler forms, which are eventually recycled. Hence, the transport of proteins to lysosomes is an important step in protein degradation. In a recent study, Clevio and colleagues explore the role of cholesterol in mediating protein degradation and ensuring neuroprotection in SCA3.

laboratory scientisy using a pipette to transfer liquid between tubes
Photo of a researcher preparing samples, courtesy of Pixabay.

Cholesterol is a well-known biological molecule that is essential to cells for regulating various processes. However, abnormally elevated levels of cholesterol are associated with heart disease, and its production is the target of pharmacological therapies. As with proteins, homeostatic fine-tuning of cholesterol levels is maintained by a balance of production and degradation.  In many neurodegenerative disorders, such as Alzheimer’s disease and Huntington’s disease, cholesterol metabolism and turnover is impaired.  The cholesterol biosynthetic pathway facilitates production and its metabolism is mediated by an enzyme called cholesterol 24-hydroxylase (CYP46A1). CYP46A1 converts cholesterol to 24-hydroxycholesterol, a form capable of crossing the blood-brain barrier. This conversion allows the efflux of cholesterol from neurons. CYP46A1 is, therefore, necessary for cholesterol efflux and the efflux of cholesterol activates the cholesterol biosynthetic pathway. The cholesterol biosynthetic pathway produces many precursors important for protein transport and autophagy.

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