JUN 01, 2020 6:20 PM PDT

New Path to Gene Therapy for ALS

WRITTEN BY: Amanda Mikyska

Video: Todd Cohen, PhD (UNC) discusses GA protein accumulation.  At the time of this video promising research was attempting to rid the cell of GA proteins by pulling them apart.  The new research from Thomas Jefferson University looks at how to avoid the accumulation of GA proteins, to begin with. 

 

Researchers at Thomas Jefferson University have found a new path for Amyotrophic Lateral Sclerosis (ALS) therapies to explore.  In a paper published this spring, they show that protecting against the degradation of a protein, SV2, that precedes the actual cause of neuronal cell death, protects the neuron's ability to transmit signals.  

Neurotransmitter vesicles also called synaptic vesicles, regulate voltage channels on neurons so that signals can reliably and accurately be passed through the body.  The body closely monitors these vesicles' health because, without their regulation, neurons break, muscles atrophy, and signals through the body are spastic and unreliable.  

In people with inherited ALS, these neurotransmitter vesicles are damaged by a genetic mutation on chromosome 9, which causes an overproduction of poly‐glycine‐alanine, or "GA" protein, which collects in the cell.  These GA protein piles travel to the dendrites and axons where they sabotage the regulation of neurotransmitter vesicles and allow excess calcium into the cell.  Too much calcium causes the neuron to misfire signals to the next neuron, and eventually kills it. 

Synaptic Vesicle Protein 2 (SV2) is essential in priming neurons to transmit low-frequency signals, regulating overall signal transmission.  Researchers at Thomas Jefferson University found that calcium toxicity ultimately causes death to neurons, but the degradation of regulating proteins, specifically SV2, is the gateway to calcium toxicity.  

The researchers, led by Dr. Brigid Jensen, confirmed this order of breakdowns in the cell in cultured motor neurons, mice, and stem cells from ALS patients that were programmed to develop into motor neurons.  In the cultured motor neurons, they found that genetic intervention that increases SV2 production prevents GA protein from accumulating and killing the cell, ultimately improving the neurons' health and longevity.  

Like other gene-therapies, this path shows promise but faces a long road ahead of trials and proof-of-concept studies.  Researchers hope that by intervening in ALS patients early, less damage will be done to their nervous system, and over a more extended period. 

 

Sources: Custer et. al., Jensen et. al., ScienceDaily, Tseng et. al., UNC Science Shorts

About the Author
  • Amanda graduated from the University of Massachusetts Boston with a degree in Biology. After working in research on creating biochemicals from genetically engineered yeast, she started freelance science writing while traveling the world. Now, Amanda is a Lab Manager and Research Assistant at the the University of Central Florida, studying the molecular phylogeny of parasitic wasps. She writes about the latest research in Neuroscience, Genetics & Genomics, and Immunology. Interested in working on solutions for food/water security, sustainable fuel, and sustainable farming. Amanda is an avid skier, podcast listener, and has run two triathlons.
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