Link Confirmed Between Protein Mutation and ALS

An international team of researchers definitively confirmed the link between kinesin family member 5A (KIF5A) and amyotrophic lateral sclerosis (ALS). The gene, which was previously connected to 2 rare neurologic disorders, regulates proteins that act as intracellular motors, according to a press release from the National Institutes of Health (NIH).

For the first time, the new findings outline how KIF5A mutations interrupt the transport of proteins up and down axons that connect nerve cells in the brain and spine, resulting in ALS, according to the study published by Neuron.

The study was funded by the NIH along with several public and private organizations, according to the release.

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The researchers conducted a genome-wide association study and analyzed variants through next-generation sequencing. In total, more than 125,000 samples were analyzed, making it the largest ALS study ever performed, according to the release.

“The extraordinary teamwork that went into this study underlines the value of global, collaborative science as we seek to better understand devastating diseases like ALS,” said Richard J. Hodes, MD, director of the National Institute on Aging. “These types of collaborative data collection and analysis are important in identifying the pathways underlying disease and in developing approaches to treatment and prevention.”

Mutations in the kinesin family of proteins have been linked to ALS, Parkinson disease, and Alzheimer disease. It has also been associated with hereditary spastic paraplegia type 10 and Charcot-Marie-Tooth Type 2, which are rare neurodegenerative diseases characterized by muscle weakness, stiffness, and spasticity.

Researchers previously hypothesized a link between KIF5A mutations with ALS but lacked proof until this new study, according to the NIH.

“Axons extend from the brain to the bottom of the spine, forming some of the longest single cellular pathways in the body,” said lead researcher Bryan Traynor, MD, PhD, of the Intramural Research Program of the NIA. “KIF5A helps to move key proteins and organelles — specialized parts of cells -- up and down that axonal transport system, controlling the engines for the nervous system’s long-range cargo trucks. This mutation disrupts that system, causing the symptoms we see with ALS.”

Although these results are groundbreaking, the researchers caution that there is still much work to be done to understand ALS and develop treatments.

“While this is unlikely to be a very common genetic cause for ALS, it identifies important new directions to explore possible future gene therapies,” Dr Traynor said.

Next steps include additional studies that examine the frequency and location of KIF5A mutations and determine what is being disrupted. The authors hope to uncover the portion of axonal transport that is crucial for cell maintenance, according to the release.