Cell Cleaning Mechanism Has Dual Role in ALS, Study Finds

Cell Cleaning Mechanism Has Dual Role in ALS, Study Finds

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.

6 comments

  1. Charlie says:

    “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.”

    Yes, very interesting. Problem is: By the time you go to the doctor because you know and accept something is not at all right, the disease is well down the track.

    Once again, why would someone get treatment when they are asymptomatic?
    Newly diagnosed pALS are virtually already dangerously progressed.

  2. Charlie says:

    “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.”

    Exactly.

    Researchers are approaching this from an ineffective angle.

  3. E. Worth says:

    Then it seems an appropriate follow up study would be to induce autophagy and couple novel anti-inflammatory measures. Any thoughts on this?

  4. E. Worth says:

    In my opinion, the problem with this study and many others is they are one dimensional. It’s like a dentist drilling a cavity out of a tooth and then quitting,declaring that drilling a cavity out does not work against cavities because they come back. Cheap and uninspiring science.

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