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Sep 10

Research Bit: Mechanisms of protein dysfunction in ALS

Research Bits
The Packard Center welcomed Darryl Bosco from the University of Massachusetts to a recent Investigator's meeting.

Date: September 10, 2021

Presenter: Darryl Bosco, PhD

Talk Title: Mechanisms of protein dysfunction in ALS

What was the question being asked?

ALS disease-linked mutations affect protein structure and function, which can lead to the accumulation of pathogenic aggregates and the loss-of-function. The Bosco lab is investigating pathogenic mechanisms of ALS-associated proteins (e.g., SOD1, FUS/TLS, profilin-1, and TDP-43) using a multidisciplinary approach involving biochemistry, cell biology, biophysics and in vivo model systems.

Why is this important for ALS research?

The genes associated with ALS encode proteins that manage homeostasis, RNA-binding, and the cytoskeletal. This project is focused on profilin and FUS in microglia to examine how mutations occur at the molecular level.

What was the take-home message?

Recent work in the Bosco’s lab has found mutations that lead to the misfolding of some ALS-associated proteins (i.e., profilin, SOD), which destabilize the protein and lead to proteasomal turn-over and reduced levels of proteins at steady state, as well as dysregulation of actin polymerization and autonomous effects on microglia. The mutations of other classes of proteins with low-complexity domains (i.e., FUS and TDP) do not affect the physical and chemical properties in the cell; however, other cellular environments and factors play a larger role in the phase-separation of FUS, which can be used to understand FUS-mediated pathogenesis.

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

This work could be used to screen for small-molecules (i.e., pharmacological chaperones) and to develop biologics against toxic, misfolded proteins.

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