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Aug 13

Research Bit: Constitutively hyperactive SARM1 mutants in ALS

Research Bits
The Packard Center welcomed Michael Coleman from the University of Cambridge to a recent Investigator's meeting

Date: August 13, 2021

Presenter: Michael Coleman, PhD

Talk Title: Constitutively hyperactive SARM1 mutants in ALS

What was the question being asked?

How do mutations in SARM1 contribute to the degeneration observed in ALS?

Why is this important for ALS research?

SARM1 is a protein that is strongly implicated in the degeneration and regeneration of neurons. When a neuron is injured (chemically or physically), a process called Wallerian Degeneration takes place. This is essentially a very precise form of pruning that trims off all the dying/dead parts of a neuron so that it can regenerate in a healthy manner. SARM1 promotes Wallerian Degeneration, although it can be quite damaging to cells if it becomes too active.

What was the take-home message?

There are some SARM1 variants in ALS patients that are hyperactive, and this alters important metabolic pathways significantly. This in turn leads to an increase in the vulnerability of neurons, meaning they die with even slight changes to their environment. In other words, the knife’s edge that neurons normally tread on becomes even thinner.How do you think the results of this study might impact future approaches to the treatment of ALS?

How do you think the results of this study might impact future approaches to the treatment of ALS?

As we learn more about the fundamental function of SARM1, as well as how ALS-related mutations alter its function, we can better understand how neurons as a whole are affected by any kind of cellular injury. Down the road, the goal is two-fold: to assess whether normal SARM1 function is altered in ALS patients, and to develop therapies that prevent SARM1 from becoming hyperactive following neuronal injury.

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