Buchan Lab Identifies New Pathway for Clearing a Key Protein Linked to ALS
Amyotrophic lateral sclerosis, commonly known as ALS or Lou Gehrig's disease, is a fatal neurodegenerative disease that destroys the motor neurons controlling movement and breathing. A defining feature of ALS — present in more than 97% of cases — is the abnormal buildup of a protein called TDP-43 in the wrong part of neurons. Normally, TDP-43 does its job inside the cell's nucleus, helping to manage genetic information. In ALS, however, it escapes into the cytoplasm, where it clumps together and becomes toxic. One promising therapeutic strategy is finding ways to help cells clear this mislocalized TDP-43 before it causes damage — but exactly how cells normally accomplish this has been poorly understood and debated.
A new study from the Buchan Lab in the Department of Molecular and Cellular Biology at the University of Arizona, published in the Journal of Cell Biology, sheds important light on this question. Led by graduate students Aaron Byrd and Lucas Marmorale — the latter a current lab member and recent recipient of a prestigious NIH F31 fellowship — the work identifies two molecular players, a protein-tagging enzyme called NEDD4 and a cellular machinery complex called ESCRT, as key drivers of TDP-43 clearance. The team found that NEDD4 physically interacts with TDP-43 and attaches small chemical tags (called ubiquitin) to it, essentially marking it for disposal. The ESCRT machinery then recognizes these tags and helps shuttle TDP-43 into specialized compartments within the cell called multivesicular bodies, where it can be degraded. Importantly, boosting NEDD4 activity reduced TDP-43 toxicity, while disabling either NEDD4 or ESCRT caused TDP-43 to accumulate and form toxic clumps — findings that held up in yeast, human cell lines, and human neurons derived from stem cells.
The study also uncovered a potentially important feedback problem: when TDP-43 builds up beyond a certain point, it appears to impair the very cellular machinery responsible for clearing it, creating a vicious cycle that may contribute to ALS progression. The researchers also observed unusual, oversized compartments forming in cells with elevated TDP-43 levels, suggesting that TDP-43 pathology may disrupt normal cellular trafficking in ways that have not been fully appreciated. Together, these findings point toward NEDD4 and the endolysosomal clearance pathway as potential targets for future ALS therapies, and raise new questions about how this disposal route intersects with the broader biology of neurodegeneration.