Researchers identify cellular traffic jams in rare neurological disease

Researchers at McGill University, led by Professor Alanna Watt of the Department of Biology, have identified previously unknown changes in brain cells affected by neurological disease. Their research, published in eLifecould pave the way for future treatments against the disease.

Spinocerebellar ataxia type 6, known as SCA6, is a rare neurological disease that disrupts the function of a part of the brain called the cerebellum, leading to difficulty with movement and coordination. This disease results from genetic mutations, with symptoms appearing in adulthood and worsening over time, and currently has no cure.

While scientists have long known that SCA6 is characterized by changes in the cerebellum, the part of the brain that regulates motor movement and balance, the precise mechanisms of these changes and how they might contribute to the onset and The progression of SCA6 is not fully understood.

The study looked at mouse models for SCA6, mice that were genetically engineered with the same mutations as human SCA6 patients and had movement problems consistent with the disease. Tissue samples from SCA mice revealed striking and never before observed abnormalities in the endosomal systems of their cells.

“Cells are busy places with a lot going on, so it’s crucial that they transport proteins and molecules to the right place and at the right time,” explained Anna Cook, a former McGill doctoral student. researcher who is the first author of the study. “But in SCA6, this system goes awry. Just as cars can get stuck in traffic, proteins and molecules can get stuck in the transport machinery within certain cells.”

To see if endosomal deficits could be corrected, researchers tested a drug called 7,8-DHF and found that the compound corrected cellular abnormalities, allowing misplaced proteins to get where they needed to go. “This drug effectively acts like a traffic cop,” Watt said. “This restarts trafficking, allowing key signaling molecules to reach cellular locations where they are needed to function.”

“As there is currently no cure for SCA6, new information about the pathological changes of the disease is essential to help develop new drugs and treatments,” Cook said. “This preclinical research is exciting not only because it sheds light on some of the fundamental mechanisms of this disease, but also because it highlights an aspect of the disease that we have shown can be targeted therapeutically.”

The Watt lab continues to build on this work to identify disease mechanisms and potential treatments for SCA6 and other cerebellar diseases. Anna Cook is now a postdoctoral researcher at the University of Oxford, where she studies dopamine signaling in healthy and diseased brains.