Nemo-like kinase reduces mutant huntingtin levels and mitigates Huntington’s disease
| Autor: | Ruiling Wang, Yuchen Li, Susumu Mori, Athanasios S. Alexandris, Qianwei Ren, Mali Jiang, Qi Peng, Juan C. Troncoso, Fanghan Yang, Jen Li Dong, Hao Gu, Janghoo Lim, Jared Lebron, Emma Whela, Zhipeng Hou, Hongshuai Liu, Ronald Wang, Xiaoyan Zhang, Christopher A. Ross, Nicolas Arbez, Tamara Ratovitski, Wenzhen Duan |
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| Rok vydání: | 2020 |
| Předmět: |
Dopamine and cAMP-Regulated Phosphoprotein 32
Proteasome Endopeptidase Complex Huntingtin Protein Serine-Threonine Kinases Biology medicine.disease_cause Serine Mice 03 medical and health sciences 0302 clinical medicine Huntington's disease Ubiquitin Genetics Huntingtin Protein medicine Animals Humans Phosphorylation Molecular Biology Genetics (clinical) 030304 developmental biology Neurons 0303 health sciences Mutation Kinase Brain General Medicine medicine.disease Corpus Striatum Cell biology Neostriatum Disease Models Animal Huntington Disease biology.protein General Article Atrophy 030217 neurology & neurosurgery |
| Zdroj: | Hum Mol Genet |
| ISSN: | 1460-2083 0964-6906 |
| Popis: | Nemo-like kinase (NLK), an evolutionarily conserved serine/threonine kinase, is highly expressed in the brain, but its function in the adult brain remains not well understood. In this study, we identify NLK as an interactor of huntingtin protein (HTT). We report that NLK levels are significantly decreased in HD human brain and HD models. Importantly, overexpression of NLK in the striatum attenuates brain atrophy, preserves striatal DARPP32 levels and reduces mutant HTT (mHTT) aggregation in HD mice. In contrast, genetic reduction of NLK exacerbates brain atrophy and loss of DARPP32 in HD mice. Moreover, we demonstrate that NLK lowers mHTT levels in a kinase activity-dependent manner, while having no significant effect on normal HTT protein levels in mouse striatal cells, human cells and HD mouse models. The NLK-mediated lowering of mHTT is associated with enhanced phosphorylation of mHTT. Phosphorylation defective mutation of serine at amino acid 120 (S120) abolishes the mHTT-lowering effect of NLK, suggesting that S120 phosphorylation is an important step in the NLK-mediated lowering of mHTT. A further mechanistic study suggests that NLK promotes mHTT ubiquitination and degradation via the proteasome pathway. Taken together, our results indicate a protective role of NLK in HD and reveal a new molecular target to reduce mHTT levels. |
| Databáze: | OpenAIRE |
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