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Cited by 21Genetic Neurodegenerative DiseasesGenetics and Neurodevelopmental DisordersAmyotrophic Lateral Sclerosis Research

Nemo-like kinase is a novel regulator of spinal and bulbar muscular atrophy

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Todd, Tiffany W, Kokubu, Hiroshi, Miranda, Helen C, Cortes, Constanza J, La Spada, Albert R, Lim, Janghoo·2015·eLife
DOI 10.7554/elife.08493PMC PMC4577982
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Abstract

Spinal and bulbar muscular atrophy (SBMA) is a progressive neuromuscular disease caused by polyglutamine expansion in the androgen receptor (AR) protein. Despite extensive research, the exact pathogenic mechanisms underlying SBMA remain elusive. In this study, we present evidence that Nemo-like kinase (NLK) promotes disease pathogenesis across multiple SBMA model systems. Most remarkably, loss of one copy of Nlk rescues SBMA phenotypes in mice, including extending lifespan. We also investigated the molecular mechanisms by which NLK exerts its effects in SBMA. Specifically, we have found that NLK can phosphorylate the mutant polyglutamine-expanded AR, enhance its aggregation, and promote AR-dependent gene transcription by regulating AR-cofactor interactions. Furthermore, NLK modulates the toxicity of a mutant AR fragment via a mechanism that is independent of AR-mediated gene transcription. Our findings uncover a crucial role for NLK in controlling SBMA toxicity and reveal a novel avenue for therapy development in SBMA.

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  • NLK expression in mouse delays SBMA disease progression but cannot completely prevent SBMA phenotype onset.

    “Taken together, NLK expression in mouse delays disease progression but cannot completely prevent SBMA phenotype onset [51].”

    From Nemo-Like Kinase in Development and Diseases: Insights from Mouse Studies (2020) · cites this paper as [51]

    The Discussion says that a 50% reduction in NLK expression may delay disease progression but cannot completely prevent the full SBMA phenotype. The claim omits the reduction and attributes the delay to NLK expression itself; the Discussion instead says NLK normally promotes the disease condition. (LLM, conf=0.87)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • Nlk haploinsufficiency (Nlk+/−) is protective in several neurodegenerative disease models, including TDP43-overexpressing mice.

    “Conditional Nlk knockout in adult animals is well-tolerated, however (59), and Nlk haploinsufficiency (Nlk+/−) is protective in several neurodegenerative disease models, including TDP43-overexpressing mice (15–18).”

    From Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS (2025) · cites this paper as [18]

    The Results (page unavailable) report that loss of one Nlk copy improves phenotypes and extends survival in an SBMA mouse model. The Discussion (page unavailable) also discusses NLK in SCA1, citing a previous publication. Our copy does not report protection in TDP43-overexpressing mice, so that example is unsupported by this source. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • NLK phosphorylates AR and ataxin-1, the proteins mutated to cause SBMA and SCA1, respectively.

    “We have previously reported that NLK phosphorylates AR and ataxin-1, the proteins mutated to cause SBMA and SCA1, respectively”

    From Reduction of nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43–related neurodegeneration (2023) · cites this paper as [8]

  • Phosphorylation of AR and ataxin-1 contributes to pathogenicity.

    “and that phosphorylation of these proteins contributes to pathogenicity (7, 8).”

    From Reduction of nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43–related neurodegeneration (2023) · cites this paper as [8]

  • Deletion of NLK could rescue muscle atrophy, motor neuron phenotypes, and extend the lifespan of heterozygous NLK mice compared to control mice in an SBMA model.

    “Deletion of NLK could rescue the muscle atrophy, as well as motor neuron phenotypes, and furthermore extend the lifespan of the heterozygous NLK mice compared to control mice.”

    From Nemo-Like Kinase in Development and Diseases: Insights from Mouse Studies (2020) · cites this paper as [51]

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Authors
Todd, T. W., Kokubu, H., Miranda, H. C., Cortes, C. J., La Spada, A. R., & Lim, J.
Affiliations
  • Yale University (US)
  • University of California San Diego (US)
  • Departments of Cellular and Molecular Medicine, Neurosciences, and Pediatrics, Division of Biological Sciences, Institute for Genomic Medicine, Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, United States
Corresponding author
Lim, Janghoo
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2015-08-26
Volume
4
Pages
e08493-e08493
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.08493
PMC
PMC4577982
OpenAlex
W2112211495
Cited by
21
References
5
Citations by year
2025: 4 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 1 · 2020: 4 · 2018: 2 · 2017: 2 · 2016: 1
FWCI
0.78
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institute of Neurological Disorders and Stroke (F31 NS081811, R00 NS064146, R01 NS083706, R01 NS041648)
  • Brain and Behavior Research Foundation (Young Investigator Award)
  • Alfred P. Sloan Foundation (Sloan Research Fellowship)
  • National Multiple Sclerosis Society (Pilot Grant)
  • Muscular Dystrophy Association (Basic Research Grant)
  • Charles H. Hood Foundation (Child Health Research Award)
  • National Ataxia Foundation (Research Grant)
  • Yale University (Yale Scholar Award)
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 › Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
Nemo-like kinase, spinal and bulbar muscular atrophy, androgen receptor, polyglutamine expansion, protein phosphorylation, protein aggregation, pathogenesis, lifespan extension, neuromuscular disorders
MeSH terms
Animals, Cell Line, Drosophila, Histocytochemistry, Humans, Muscles, Phosphorylation, Protein Processing, Post-Translational, Receptors, Androgen, Spinal Cord, Survival Analysis, Protein Serine-Threonine Kinases, Mitogen-Activated Protein Kinases, Muscular Disorders, Atrophic, Mice

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