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UA, Barrow Researchers Explain ALS Key Protein Breakdown

Published: Thursday, December 28, 2017 - 7:30am
Updated: Thursday, December 28, 2017 - 8:24am
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No cure exists for Lou Gehrig's disease, a fatal neuromuscular illness affecting tens of thousands of Americans. But scientists may have found how a key protein helps drive its degenerative progress.

At the heart of amyotrophic lateral sclerosis (ALS) lies a communication breakdown between motor neurons and the muscles they control.

Experts only partly understand this process, but a study published in the Oct. 3 issue of Cell Reports may have found a key break in the circuit: inhibition of a protein called Hsc70 that normally helps synaptic vesicles – tiny sacs at the ends of motor neurons – dispatch their chemical telegrams.

"These are key structures within the cell that ensure that neurotransmitters travel between neurons and muscles efficiently and correctly," said co-author Daniela Zarnescu of the University of Arizona Department of Molecular and Cellular Biology.

Hsc70 inhibition begins with another protein, a known ALS culprit called TDP-43. When TDP-43 malfunctions in ALS, it traps a number of important molecules – RNAs and proteins, including Hsc70 – in cells' jellylike cytoplasm, interfering with their ability to function.

But what exactly goes on, and how it might be treated, remains unclear.

This new study helps explain how faulty TDP-43 alters Hsc70's function and expression.

"That gives us an insight into how we could potentially fix or restore the function of this molecule in motor neurons from patients and try to improve the communication between these cells – neurons and muscles – and eventually restore muscle function," Zarnescu said.

The UA team first identified troublesome proteins using a fruit fly model to mimic a simplified version of ALS. They then worked with the Barrow Neurological Institute to see if the pattern repeated in human cells.

BNI's Sattler Lab can make motor neurons by reprogramming patient skin cells back to a state akin to that of embryonic stem cells. These pluripotent cells can then specialize into motor neurons.

Zarnescu said improving the protein's performance could offer a promising target for ALS therapy. She added that the findings could also find applications in treating other neurodegenerative diseases, such as dementia or Alzheimer's disease.

EDITOR'S NOTE: This story has been updated to correct the name of the research group that worked with the University of Arizona.