As people live longer, more are affected by Alzheimer’s and related brain diseases, which place a growing burden on healthcare. These conditions are often linked to the buildup of broken or misfolded proteins in brain cells. One protein in particular, TDP43, breaks into fragments that are especially harmful and are found in diseases like ALS and frontotemporal dementia.

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Our lab at Texas Woman’s University studies how cells remove these harmful fragments through natural cleanup systems. We’ve discovered that the site where a protein is cut affects its tendency to clump together and cause damage, and that different cellular pathways recognize and clear these fragments. In addition to two previously identified pathways, we are now working to characterize a third protein quality control system that helps prevent this buildup. Collectively, our work shows that cells rely on a multilayered defense network to guard against protein aggregation linked to neurodegeneration.

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This work is supported by the National Institute of Neurological Disorders and Stroke.