RNA modification ‘pivotal’ for protein linked to neurodegeneration in ALS

TDP-43 is known as the “Goldilocks” protein. Too much or too little can cause cell death.

8:50 AM

Author | Noah Fromson

brain drawing blue grey shading yellow spots
Jake Dwyer, Justine Ross, Michigan Medicine

Nearly 100% of cases of amyotrophic lateral sclerosis—the progressive, fatal neurodegenerative disease known as ALS or Lou Gherig’s disease — involve the buildup of a protein called TDP-43.

Scientists know that TDP-43, which helps regulate processing of RNA, may be responsible for the death of nerve cells in ALS and frontotemporal dementia. Previous studies by investigators at Michigan Medicine found that too much TDP-43 in the cells of patients caused the RNA to become very unstable.

And a study published in Molecular Cell suggests that a common modification to RNA plays a pivotal role in TDP-43-related neurodegeneration in ALS.

SEE ALSO: The Rogue Proteins Behind Lethal Neurodegenerative Disorders

Researchers at Michigan Medicine focused on the most abundant RNA modification, a methylation event known as m6A. Through sequencing analysis, investigators showed that methylation strongly influences the binding of TDP-43 to its RNA targets. They also observed highly abundant RNA methylation in the end-stage tissues of patients with ALS. 

“This is an RNA modification that has escaped our attention in the past, and yet it is rampant in patients with ALS,” said Sami Barmada, M.D., Ph.D., senior author and Angela Dobson Welch and Lyndon Welch Research Professor of Neurology at University of Michigan Medical School. “Despite the fact that we see all this RNA methylation, it’s hard to say exactly what it means,” Barmada said. “It’s like watching the end of the movie and then trying to work out the plot. We see RNA methylation, TDP-43 buildup and loss of brain cells, but how are these connected?”

Previous studies suggest that total levels of m6A in the nervous system rise with age and that (some) neurodegenerative diseases are characterized by RNA hypermethylation. Importantly, RNA methylation is modified by environmental exposure.

Its presence in ALS, Barmada says, opens up a wide range of possibilities for research of a disease that is intimately linked to environmental exposure, as demonstrated by Stephen Goutman, M.D., M.S., and Eva Feldman, M.D., Ph.D., at Michigan Medicine.

Additional authors include Michael McMillan Ph.D., Nicolas Gomez M.S., Caroline Hsieh M.S., Michael Bekier Ph.D., Xingli Li Ph.D., Roberto Miguez M.S. and Elizabeth M. H. Tank Ph.D., all of University of Michigan.

Funding was provided by the NIH/NINDS, NIH/NIA, the family of Angela Dobson Welch and Lyndon Welch, the Robert Packard Center for ALS Research and the Alfred A. Taubman Medical Research Institute. 

Barmada is a member of the Scientific Advisory Board for the Robert Packard Center for ALS Research

Paper cited: “RNA methylation influences TDP43 binding and disease pathogenesis in models of amyotrophic lateral sclerosis and frontotemporal dementia,” Molecular Cell. DOI: 0.1016/j.molcel.2022.12.019


More Articles About: Lou Gehrig's (ALS) Neurological Disorders Neurodegenerative Disorder All Research Topics
Health Lab word mark overlaying blue cells
Health Lab

Explore a variety of healthcare news & stories by visiting the Health Lab home page for more articles.

Related
Health Lab
A New Clue in the Mystery of ALS, Frontotemporal Dementia
Michigan Medicine researchers identify a potential therapeutic target for neurodegenerative conditions using animal models.
Featured News & Stories surgeons in operating room
Health Lab
A unique approach to transplantation for liver malignancies
A Michigan Medicine transplant specialist examines different ways of caring for patients with liver cancer.
vial of blood with blue background cell floating
Health Lab
Hitting the mark
University of Michigan Rogel Cancer Center researchers are unraveling its nuances, advancing enabling technologies, advocating for patients and figuring out how to ethically integrate this technology into clinical care.
cells floating pink purple green
Health Lab
Scientists develop new model for understanding sudden death in epilepsy
Researchers at the University of Michigan have developed a model for studying one type of familial epilepsy, opening the door to understanding—and eventually targeting—the mechanisms that lead to the disorder and its associated fatalities.
green circle cells close together highlighted in yellow
Health Lab
Solving a sticky, life threatening problem
Michigan Medicine researchers have zeroed in on C. auris’ uncanny ability to stick to everything from skin to catheters and made a startling discovery.
stork with baby in bag with dollar sign
Health Lab
Childbirth associated with significant medical debt
Postpartum individuals are more likely to have medical debt than those who are pregnant, suggests a Michigan Medicine led study that evaluated collections among a statewide commercially insured cohort of 14,560 pregnant people and 12,157 people in the postpartum period.
liver in bright green against navy background
Health Lab
Genetic variation with MASLD reveals subtypes and potential therapeutic avenues
A Michigan Medicine team of experts seeks to identify the human genetic causes of MASLD, formerly called NAFLD