Credit: National Cancer Institute
1st-ever evidence-based description of neuronal protein clumps thought to be important in Amyotrophic Lateral Sclerosis (ALS) announced today. These clumps are toxic to the type of neurons that die in patients with ALS. This research could be a crucial step toward developing drugs to stop the creation of the clumps and stem the progression of the disease.
“This study is a big breakthrough because it sheds light on the origin of motor neuron death and could be very important for drug discovery,” Nikolay Dokholyan, PhD. Patients with ALS suffer gradual paralysis and early death as a result of the loss of motor neurons, which are crucial to moving, speaking, swallowing, and breathing.
The study focuses on a subset of ALS cases – 1 to 2% associated with variations in protein SOD1. However, even in patients without mutations in their SOD1 gene, this protein has been shown to form potentially toxic clumps. The protein forms temporary clumps trimers capable of killing motor neuron-like cells grown in the laboratory.
Proctor spent 2 years developing a custom algorithm to determine the trimers’ structure. Once the trimers’ structure was established, the team spent several more years developing methods to test the trimers’ effects on motor neuron-like cells grown in the laboratory. The results were clear: SOD1 proteins that were tightly bound into trimers were lethal to the motor neuron-like cells, while non-clumped SOD1 proteins were not.
The team plans to further investigate the “glue” that holds the trimers together in order to find drugs that could break them apart or keep them from forming.
In addition, these findings could help shed light on other neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s. “There are many similarities among neurodegenerative diseases,” said Dokholyan. “What we have found here seems to corroborate what is known about Alzheimer’s already, and if we can figure out more about what is going on here, we could potentially open up a framework to be able to understand the roots of other neurodegenerative diseases.” http://www.eurekalert.org/pub_releases/2015-12/uonc-nso122315.php
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