Enhancing Cellular Cleanup Mechanism Helped ALS Mice

Eliminating the XBP1 protein enhanced cellular cleanup, saved nerve cells and prolonged survival in female ALS mice

by Quest Staff on September 24, 2009 - 5:00pm

New research supports strategies that augment a natural process in the nervous system called autophagy – a cellular cleanup and garbage-disposal system — as a possible therapeutic avenue in amyotrophic lateral sclerosis (ALS).


Autophagy (literally "self-eating") is activated when large amounts of debris and abnormal cellular components require destruction.


Female mice with an ALS-like disease that underwent genetic manipulation that enhanced garbage removal in their nervous systems fared better than female mice without this treatment. For some reason, however, male ALS mice weren't helped.


The study was coordinated by MDA grantee Claudio Hetz at Harvard University's School of Public Health in Boston and the University of Chile in Santiago, and Laurie Glimcher, at Harvard Medical School and the University of Chile. The findings were published online Sept. 17, 2009, in Genes & Development.


Robert Brown, who directs the MDA ALS Center at the University of Massachusetts Memorial Medical Center in Worcester, was also on the study team.


About ALS


ALS is a disease in which the motor neurons, muscle-controlling nerve cells in the brain and spinal cord, are lost, causing progressive paralysis. The disease usually begins in middle age or later and affects males and females, although it's slightly more common in males.


About 10 percent of the time, the disease is "familial" or preceded by a family history. The other 90 percent of the time, it's "sporadic," meaning it occurs without a family history.


Various mutations in the SOD1 gene on chromosome 21 are responsible for some 1 percent to 3 percent of all ALS cases. Mice with various SOD1 gene mutations are the most commonly used tool in ALS research, and they were used in this study. (The cause of sporadic ALS isn't known, so mice with this condition can't be developed.)


About the new findings


The investigators generated mice with SOD1 mutations that were genetically destined to develop ALS and also were genetically deficient in a protein called XBP1 in their nervous systems.


XBP1 is believed to help cells respond to various types of physiologic stress, so the researchers had expected cells without it to fare worse than cells with it.


To their surprise, however, female ALS mice missing XBP1 in their nerve cells developed ALS later and lived a highly significant average of 22 days longer than ALS mice with normal XBP1 levels. (Male ALS mice without XBP1 didn't show a significant increase in life span, but their disease wasn't worsened by the loss of XBP1.)


The researchers determined that the increase in life span of the female ALS mice and the delayed onset of ALS symptoms in these mice correlated with more autophagy in their spinal-cord nerve cells.


It appears that the loss of XBP1 flipped a regulatory switch in the cells, activating the garbage-removal system, Hetz said. The cleanup process apparently saved a significant number of nerve cells. In the absence of XBP1, Hetz said, "autophagy is induced to compensate the lack of the stress factor XBP1. This switch confers protection against ALS."


The scientists say they don't know why there's a gender difference in the response of the SOD1 ALS mice to removing XBP1 from the nervous system.


When they looked at spinal-cord samples from people with both sporadic and familial ALS, they saw evidence that autophagy had been activated, apparently as a defense mechanism against the disease. They didn't have enough samples to determine whether there was a gender difference in the patients' responses.


Meaning for patients


There is no immediate implication for patients. However, if the findings in this study are confirmed, it may prove worthwhile to develop strategies for ALS treatment that enhance autophagy.


Hetz's group in Chile, which continues to receive MDA support, is currently testing several drug candidates to enhance autophagy in mouse models of ALS and test the possible therapeutic effects on the disease.

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