NEUROLOGY

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New Genetic Mutation Link to ALS

 

KIF5A regulates part of the kinesin family of proteins that serve as tiny intracellular motors. Problems with these proteins are connected to amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, Parkinson’s disease and Alzheimer’s disease. KIF5A mutations were previously known to be connected to two other rare neurodegenerative diseases with muscle weakening, stiffening and spasticity symptoms similar to ALS: hereditary spastic paraplegia type 10 (SPG10) and Charcot-Marie-Tooth Type 2 (CMT2.) Scientists suspected KIF5A might be associated with ALS but lacked definite proof until now.

 

Now, according to an article published in Neuron (21 March 2018), Kinesin family member 5A (KIF5A), has been definitively connected to ALS. The findings identify how mutations in KIF5A disrupt transport of key proteins up and down long, threadlike axons that connect nerve cells between the brain and the spine, eventually leading to the neuromuscular symptoms of ALS.

 

According to the NIH, it took a comprehensive, collaborative effort to analyze a massive amount of genetic data to pin down KIF5A as a suspect for ALS. To zero in on KIF5A, the NIH team performed a large-scale genome-wide association study, while the University of Massachusetts team concentrated on analyzing rare variants in next generation sequence data. Over 125,000 samples were used in this study, making it by far the largest such study of ALS performed to date.

 

According to the authors, axons extend from the brain to the bottom of the spine, forming some of the longest single cellular pathways in the body, and that KIF5A helps to move key proteins and organelles 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. The authors cautioned that the discovery, while exciting, still leaves much more work to be done. The authors added that next steps for the project include further study of the frequency and location of mutations within KIF5A and determining what cargos are being disrupted.

 

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