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Nov 8

Research Bit: Role of autophagy-inducing kinases ULK1/2 in the disassembly of stress granules

Research Bits
The Packard Center welcomed Mondira Kundu, M.D., Ph.D, from St. Jude Children's Research Hospital to a recent Investigator's Meeting.

Meeting Date: November 8, 2019

Presenter: Mondira Kundu, MD, PhD

Talk Title: Role of autophagy-inducing kinases ULK1/2 in the disassembly of stress granules


What was the question being asked?

ULK1/2 have previously been implicated in the process of autophagy, one of the major protein degradation pathways in the cell and essential to maintain proper function. Importantly, autophagy is also a pathway by which defective or aberrant organelles, including stress granules, can be cleared from the cell. While normally protective in helping a cell recover from stress, membraneless organelles, termed stress granules, are thought to evolve into pathological aggregates seen in end-stage disease during the pathogenesis of neurodegeneration. Interestingly, the interactome of ULK1 contains many proteins associates with stress granules, many of which have been previously shown to associate with proteins involved in ALS pathogenesis. Furthermore, inhibition of ULK1 impairs the ability of stress granules to recover following exogenous stressors, a phenomenon reminiscent of that seen with many ALS associated RNA binding proteins. The Kundu lab now seeks to understand the precise role of ULK1/2 in stress granule biology, and in particular how this role may relate to proteins involved in the pathogenesis of ALS and related neurodegenerative diseases.

Why is this important for ALS research?

It is commonly thought that the persistence of stress granules, either due to mutations in stress granule related proteins and/or defects in autophagy, can lead to the formation of pathological fibrils and aggregates commonly observed in neurodegenerative disease. However, the mechanisms governing stress granule dynamics still remain poorly understood. The research in the Kundu lab seeks to shed light on this process by studying a protein ULK1/2 that has been shown to interact with both stress granule and autophagy related proteins. 

What was the take-home message?

The Kundu lab has identified an interaction between ULK1/2 and VCP, a protein implicated in ALS and related neurodegenerative diseases. Specifically, ULK1/2 is involved in the phosphorylation of VCP, which ultimately impacts the stress granule related dynamics of VCP.

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

A comprehensive understanding of the mechanisms underlying stress granule dynamics is essential towards the identification of potential therapeutic strategies that may protect against aberrant or prolonged stress granule formation, a process thought to be linked to multiple neurodegenerative diseases.

Alyssa Coyne, Ph.D
Postdoctoral Fellow, Rothstein Lab
The Johns Hopkins University School of Medicine

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