Identified biochemical switches that could be activated to treat muscle and brain disorders – ScienceDaily


Scientists from St. Jude Children's Research Hospital have discovered that the ULK1 and ULK2 enzymes play a key role in the demolition of cellular structures called stress granules, the persistence of which leads to the toxic accumulation of proteins that kill muscle and brain cells. This accumulation is fundamental for the pathology of three related diseases: included body myopathy (IBM), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).

IBM causes weakness in the muscles of the arms and legs. ALS, also known as Lou Gehrig's disease, causes paralysis due to the death of nerve cells that control voluntary muscles. FTD is a form of dementia that damages the areas of the brain associated with personality, behavior and language.

Led by St. Jude researcher Mondira Kundu, M.D., Ph.D., an associate member of the St. Jude pathology department, the team published their findings online in the journal Molecular cell.

Stress granules are biological "storm shelters" that temporarily protect molecules and genetic proteins when the health of the cell is threatened by heat, chemicals or infections. These granules normally disassemble when stress is removed, but the mutations that cause malfunctions in the disassembly machine can make them persist. One such mutation is in a gene called VCP, and the St. Jude researchers found that ULK1 / 2 is a key activator of VCP. Thus, they believe that drugs to enhance those enzymes could help treat the pathology of IBM, ALS and FTD.

The other authors of St. Jude are Bo Wang, Brian Maxwell, Joung Hyuck Joo, Youngdae Gwon, James Messing, Ashutosh Mishra, Timothy Shaw, Amber Ward, Honghu Quan, Sadie Miki Sakurada, Shondra Pruett-Miller, Peter Vogel, Hong Joo Kim and Junmin Peng. The co-author Tulio Bertorini is with the University of Tennessee Heath Science Center. Co-author J. Paul Taylor is a researcher at Howard Hughes College and chair of the St. Jude Department of Cellular and Molecular Biology.

The research was supported by the National Institutes of Health (R01 MH115058, HL114697, R01 GM114260, R35 NS097974), by the Robert Packard Center for ALS Research and ALSAC, from the St. Jude fundraising and awareness organization.


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