Scientists Identified CLCN6 as Potential Therapeutic Target for Early-Onset Neurodegeneration

Date: November 19, 2020 American Journal of Human Genetics

Researchers at the Leibniz-Vermont State Medical Institute (FMP) and Max Delbrück Center Molecular School of Medicine (MDC) and an international team of researchers analyzed mutations in the CLCN6 gene. They found that CLCN6 mutations are associated with a new type of particularly serious neurodegenerative disease, and their results have just been published in the American Journal of Human Genetics.

About lysosomal neurodegenerative disease

Lysosomal storage diseases usually refer to many genetically determined metabolic diseases caused by incorrect or insufficient lysosome function. These organelles are important for "cell waste disposal" and the regulation of cell metabolism. If the function of the lysosome is impaired, normally degraded substances may accumulate in the affected cells, which may impair their function and eventually lead to cell death. Dysfunction of the endolysosome system is usually associated with neurodegenerative diseases, because adult neurons cannot regenerate.

The research team analyzed the gene defect of three unrelated (from Italy, Germany and the U.S) children with severe neurodegenerative diseases. They have found 3 children with the same mutation in CLCN6, which can cause severe developmental delay, mental retardation, respiratory insufficiency, visual impairment and early-onset brain atrophy, which is underlying a novel severe form of neurodegenerative disease.

Ion transporter ClC-6

ClC-6 is an encoded protein that belongs to the CCL voltage-gated chloride channel protein family. It can exchange negatively charged chloride ions between the cell and its surrounding environment and interact with various cells including intracellular vesicle acidification. The process is related.

Scientists have revealed through functional analysis that mutations in CLCN6 lead to the gain of ClC-6 function. This ion transporter mainly exists in the late endosome fused with lysosome. These organelles are responsible for the enzymatic degradation of extracellular materials and intracellular proteins that are no longer needed by the cell. Disturbances of the endolysosome system are usually associated with neurodegenerative diseases, because neurons that no longer proliferate are particularly dependent on the elimination of accumulations in the cells.

The work published in the American Journal of Human Genetics shows that over-activation of ClC-6 can lead to increased transport of chloride and protons to affected cells, leading to lysosomal dysfunction.

1. Story Source: Polovitskaya, M. M., Barbini, C., Martinelli, D., Harms, F. L., Cole, F. S., Calligari, P., ... & Rizza, T. (2020). A Recurrent Gain-of-Function Mutation in CLCN6, Encoding the ClC-6 Cl−/H+-Exchanger, Causes Early-Onset Neurodegeneration. The American Journal of Human Genetics. doi.org/10.1016/j.ajhg.2020.11.004

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