한빛사논문
- 조회697
Leon Tejwani1,2,8,†, Youngseob Jung3,8, Hiroshi Kokubu3,8, Sowmithra Sowmithra3, Luhan Ni3, Changwoo Lee1,2, Benjamin Sanders1,2, Paul J. Lee1,2, Yangfei Xiang3, Kimberly Luttik1,2, Armand Soriano4, Jennifer Yoon5, Junhyun Park1,2, Hannah Ro5, Hyoungseok Ju3,‡, Clara Liao1, Sofia Massaro Tieze1, Frank Rigo4, Paymaan Jafar-Nejad4, and Janghoo Lim1,2,3,6,7,*
1Interdepartmental Neuroscience Program, Yale School of Medicine, New Haven, CT 06510, USA.
2Department of Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA.
3Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA.
4Ionis Pharmaceuticals, Carlsbad, CA 92010, USA.
5Yale College, New Haven, CT 06510, USA.
6Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale School of Medicine, New Haven, CT 06510, USA.
7Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06510, USA.
8These authors contributed equally to this work.
†Current affiliation: Denali Therapeutics Inc., South San Francisco, CA 94080, USA.
‡Current affiliation: Neuroscience, Biopharmaceuticals R&D, AstraZeneca, Granta Park, Cambridge, CB21 6GH, UK.
*To whom correspondence should be addressed: Dr. Janghoo Lim
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 potential approach to therapy development for multiple neurodegenerative disorders.
논문정보
- Research article
- 2023년 06월 (BRIC 등록일 2023-07-26)
- 국외 연구진
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