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Cited by 15Genetic Neurodegenerative DiseasesGenetics and Neurodevelopmental DisordersLysosomal Storage Disorders Research

Nemo-like kinase reduces mutant huntingtin levels and mitigates Huntington’s disease

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Jiang, Mali, Zhang, Xiaoyan, Liu, Hongshuai, LeBron, Jared, Alexandris, Athanasios, Peng, Qi, Gu, Hao, Yang, Fanghan +14 more·2020·Human Molecular Genetics
DOI 10.1093/hmg/ddaa061PMC PMC7254850
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Abstract

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.

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  • Exogenous NLK, like endogenous NLK, is both cytoplasmic and nuclear in distribution.

    “Exogenous NLK, like endogenous NLK, is both cytoplasmic and nuclear in distribution (19).”

    From Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS (2025) · cites this paper as [19]

    The Results (page unavailable, Fig. 1C) state that transfected NLK was detected in both cytoplasmic and nuclear compartments, supporting the claim about exogenous NLK. The passage does not establish that endogenous NLK has the same distribution. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Inducing NLK in knock-out HD models resulted in attenuated brain atrophy and a reduction in mHTT aggregates.

    “In addition, inducing NLK in the knock-out HD models resulted in attenuated brain atrophy and a reduction in mHTT aggregates.”

    From Nemo-Like Kinase in Development and Diseases: Insights from Mouse Studies (2020) · cites this paper as [52]

    The Results section reports that NLK overexpression in N171-82Q HD mice attenuated brain atrophy and reduced mHTT aggregates. But these were not knock-out HD models: the separate experiment involving NLK+/− mice reduced NLK and exacerbated brain atrophy. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • NLK has a neuroprotective role in HD, since deletion of NLK caused accelerated brain dysfunction.

    “Overall, the authors were able to show that NLK has a neuroprotective role in HD, since the deletion of NLK caused accelerated brain dysfunction [52].”

    From Nemo-Like Kinase in Development and Diseases: Insights from Mouse Studies (2020) · cites this paper as [52]

    The Results (‘Genetic reduction of NLK exacerbates neuropathology in HD mice’) report that a roughly 50% reduction of NLK worsened brain atrophy and lowered DARPP32 in HD mice. The Discussion concludes that NLK has a protective role and that lower NLK levels may accelerate brain dysfunction. The study tested partial genetic reduction, not complete deletion, and hedges the acceleration claim. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Genetic reduction of NLK worsens HD brain pathology in mice.

    “Genetic reduction of NLK worsens HD brain pathology in these mice [52].”

    From Nemo-Like Kinase in Development and Diseases: Insights from Mouse Studies (2020) · cites this paper as [52]

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Authors
Jiang, M., Zhang, X., Liu, H., LeBron, J., Alexandris, A., Peng, Q., Gu, H., Yang, F., Li, Y., Wang, R., Hou, Z., Arbez, N., Ren, Q., Dong, J.-L., Whela, E., Wang, R., Ratovitski, T., Troncoso, J. C., Mori, S., Ross, C. A., Lim, J., & Duan, W.
Affiliations
  • Johns Hopkins University (US)
  • Yale University (US)
Corresponding author
Duan, Wenzhen
ORCID
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2020-04-02
Volume
29
Issue
8
Pages
1340-1352
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
DOI
10.1093/hmg/ddaa061
PMC
PMC7254850
OpenAlex
W3014284868
Cited by
15
References
6
Citations by year
2026: 1 · 2025: 5 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 2 · 2020: 2
FWCI
0.92
Type
journal article
Language
en
Open access
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations
  • Human Molecular Genetics (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
NIH (R21MH119803, R01NS088321, R01NS083706, R21NS099670, R21NS094886, R01NS082338)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
Keywords
Nemo-like kinase, Huntington's disease, mutant huntingtin, proteasomal degradation, ubiquitination, DARPP-32, striatum, brain atrophy, kinase activity, therapeutic target
MeSH terms
Huntingtin Protein, Animals, Atrophy, Brain, Corpus Striatum, Disease Models, Animal, Humans, Huntington Disease, Neurons, Phosphorylation, Neostriatum, Protein Serine-Threonine Kinases, Proteasome Endopeptidase Complex, Mice, Dopamine and cAMP-Regulated Phosphoprotein 32

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