A mechanism that cells normally use to keep them healthy was found to have a dual role in amyotrophic lateral sclerosis (ALS). While the process, called autophagy, delays disease progression in early stages, it contributes to ALS’s deadly spread through the spinal cord in later stages.
This study, “Distinct roles for motor neuron autophagy early and late in the SOD1G93A mouse model of ALS,” was published in the journal Proceedings of the National Academy of Sciencies (PNAS).
“One of the biggest barriers to treating ALS is that its progression is dynamic — many different cell types and mechanisms are involved — so treating it at one stage of the disease might have very different, and potentially harmful, consequences at a different stage,” Tom Maniatis, PhD, principal investigator at Columbia’s Mortimer B. Zuckerman Mind Brain Behavior Institute and senior author of the study, said in a news release.
Abnormal accumulation of protein aggregates inside motor nerve cells is a common feature in ALS. This triggers autophagy, a key cellular clean-up program that breaks down and disposes of protein clumps and other damaged structures within cells.
Mutations in genes involved in autophagy can drive ALS progression, as recently shown by University of Columbia geneticist David Goldstein. But whether autophagy could have an active role in ALS development was still unknown.
To address this question, Maniatis and his team used mouse models of ALS, engineered to have impaired autophagy in motor neurons.
In the absence of the cleaning mechanism, the mice’s motor symptoms progressed more rapidly in the early stages of the disease, compared to mice with normal autophagy. But in later stages, the reverse was observed — defective autophagy made the disease spread slower.
Mice lacking a normal autophagy mechanism were also seen to live longer than control mice.
“This strongly suggested that even though autophagy may initially stave off disease by suppressing protein aggregation, it eventually hastens the spread of ALS and its devastating symptoms to the rest of the spinal cord,” Maniatis said.
The rationale is that when autophagy is intact, the toxic aggregates are removed from the cells and released to the surrounding environment, triggering an inflammatory reaction. This soon spreads throughout the spinal cord, contributing to the progression of ALS.
“By the time ALS symptoms are noticeable, the disease is very far along so drugs aren’t likely to work unless we can diagnose ALS much earlier — which will be helped by understanding how mutations in autophagy genes cause ALS and affect disease progression,” Maniatis said.
“If we can find ways of treating the earlier stages of disease, rather than trying to stop it after it’s full blown, it may be possible to develop more effective therapies,” he said.
The team is currently studying the impact that mutations in genes involved in autophagy can have in ALS progression.