Modifying Cellular Stress Response as a Way To Treat ALS

An MDA-supported research team has identified a series of compounds that appear to work both alone and in combination to protect the muscle-controlling nerve cells (motor neurons) that are lost in amyotrophic lateral sclerosis (ALS).

The compounds — salubrinal, guanabenz and phenazine, as well as the previously identified methylene blue — suppress toxicity caused by flawed TDP43 protein. (Toxicity caused by abnormal TDP43 protein is found in the degenerating motor neurons of most people who have ALS that isn't caused by an SOD1 mutation.)

The researchers noted that the compounds appear to work by targeting various pathways in a critical cell survival mechanism known as the endoplasmic reticulum (ER) stress response. The endoplasmic reticulum is a cellular compartment involved in the transport of proteins and other biological substances within cells.

ER stress has been previously implicated as a likely contributor to ALS onset and progression, and the new findings suggest that therapies designed to reduce ER stress potentially may offer some benefit in ALS.

Treatment with compounds reduced ALS symptoms

In worm and zebrafish models of TDP43-associated ALS, treatment with the compounds led to less paralysis, less motor neuron degeneration and less oxidative stress than was observed in untreated animals.

In addition, treatment with methylene blue in combination with any one of the other three compounds was more effective than any single compound alone.

Guanabenz (marketed under the brand name Wytensin) is approved by the U.S. Food and Drug Administration (FDA) to treat high blood pressure. Although it's available by prescription, it's not recommended that anyone with ALS seek an off-label prescription for the drug.

MDA supported Alex Parker at the University of Montreal Hospital Research Center in Montreal, Quebec (Canada), for his work on this project.

The research team published its findings online April 5, 2013, in Neurobiology of Disease. Read the entire report, for a fee: Pharmacological Reduction of ER Stress Protects Against TDP43 Neuronal Toxicity In Vivo.

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