Scientists to study how abnormal protein drives ALS
Johns Hopkins, ALS United partner to fund research project
The Robert Packard Center for ALS Research at Johns Hopkins and ALS United will fund a preclinical study investigating how TDP-43 abnormalities contribute to amyotrophic lateral sclerosis (ALS).
The project, “Alternative Polyadenylation-Driven Subcellular RNA Mislocalization in TDP-43 Proteinopathies,” will explore the molecular mechanisms by which TDP-43 clumps, a hallmark of ALS, may drive the loss of motor neurons seen in ALS.
The researchers also aim to identify new therapeutic targets linked to these pathways.
Albert La Spada, MD, PhD, a professor at the University of California, Irvine, and Sandrine Da Cruz, PhD, group leader at the VIB–KU Leuven Center for Brain & Disease Research in Belgium, will lead the project.
“We are excited to partner with ALS United on co-funding this important research,” Christine Vande Velde, PhD, scientific director at the Packard Center, said in a center press release. “This work will advance our collective missions to change the course of this disease by engaging in breakthrough research that advances our fundamental understanding of ALS.”
How does TDP-43 influence cells?
ALS is a progressive neurodegenerative disease caused by the dysfunction and death of motor neurons, the nerve cells that control voluntary movements. While the exact causes of ALS are unknown, about 97% of patients have toxic aggregates of the TDP-43 protein in their nerve cells.
Under normal conditions, TDP-43 plays a key role in processing mRNA molecules — molecules that serve as templates for protein production — within the nucleus. For example, the protein regulates alternative polyadenylation (APA), a mechanism that enables cells to produce multiple mRNAs and, consequently, different proteins, from a single gene. This process helps different cells acquire specialized functions.
In ALS, however, TDP-43 accumulates in the cytoplasm (the fluid-filled space outside the nucleus), which disrupts RNA processing and protein production.
While the general impact of this TDP-43 mislocalization on RNA processing is well known, its specific effects on APA and how that influences where mRNAs end up within the cell remain unclear.
The researchers hypothesize that the loss of normal TDP-43 activity may alter APA patterns, causing certain mRNAs to end up in the wrong parts of the cell.
Because neurons have distinct regions that rely on tightly controlled, localized protein production to maintain their function, misplaced mRNAs could mean that the right proteins are not made where needed. This could impair neuronal signaling and health, contributing to motor neuron degeneration.
By investigating these processes, the researchers seek to uncover how TDP-43 dysfunction alters mRNA localization within cells and to identify new molecular pathways that could serve as therapeutic targets in ALS.
“This partnership with the Packard Center demonstrates ALS United’s commitment to strategic research collaboration,” said Jerry Dawson, president and CEO of ALS United. “Our members have been funding ALS research for decades, and we’ve learned that partnering with established programs like the Packard Center allows us to maximize impact while accessing world-class scientific expertise. This is one of several important research partnerships through which our members are accelerating the search for treatments and cures.”
About the Author
