Reduction of nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43–related neurodegeneration
Leon Tejwani, Youngseob Jung, Hiroshi Kokubu, Sowmithra Sowmithra, Luhan Ni, Chang‐Woo Lee, Benjamin Sanders, Jong Seo Lee, Yangfei Xiang, Kimberly P. Luttik, Armand Soriano, Jennifer Yoon, Junhyun Park, Hannah Ro, Hyoungseok Ju, Clara Liao, Sofia Massaro Tieze, Frank Rigo, Paymaan Jafar‐Nejad, Janghoo Lim
Abstract
Protein aggregation is a hallmark of many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Although mutations in TARDBP, encoding transactive response DNA-binding protein 43 kDa (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-causing (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 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 life span deficits in 2 distinct mouse models of TDP-43 proteinopathy. Because many toxic proteins can be cleared through the autophagy/lysosome pathway, targeted reduction of Nlk represents a potential approach to therapy development for multiple neurodegenerative disorders.