Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.19.049395v1?rss=1
Authors: Tejwani, L., Kokubu, H., Lee, P. J., Xiang, Y., Luttik, K., Soriano, A., Yoon, J., Park, J., Ro, H., Ju, H., Liao, C., Tieze, S., Rigo, F., Jafar-Nejad, P., Lim, J.
Abstract: Protein aggregation is a hallmark of many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Although mutations in TARDBP, encoding TDP-43, account for less than 1% of all ALS cases, TDP-43-positive aggregates are present in nearly all ALS patients, including patients with sporadic ALS (sALS) or carrying other familial ALS (fALS)-causing mutations. Interestingly, TDP-43 inclusions are also present in subsets of patients with frontotemporal dementia, Alzheimer's disease, and Parkinson's disease; therefore, methods of activating intracellular protein quality control machinery capable of clearing toxic cytoplasmic TDP-43 species may alleviate disease-related phenotypes. Here, we identify a novel function of Nemo-like kinase (Nlk) as a negative regulator of lysosome biogenesis. Genetic or pharmacological reduction of Nlk increased lysosome formation and improved clearance of aggregated TDP-43. Furthermore, Nlk reduction ameliorated pathological, behavioral, and lifespan deficits in two distinct mouse models of TDP-43 proteinopathy. Because many toxic proteins can be cleared along the autophagy-lysosome axis, targeted reduction of Nlk represents a viable approach to therapy development for multiple neurodegenerative disorders.
Copy rights belong to original authors. Visit the link for more info
Podchaser is the ultimate destination for podcast data, search, and discovery. Learn More