title: Nemo-like kinase is a novel regulator of spinal and bulbar muscular atrophy.
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.
authors: Program in Cellular Neuroscience, Neurodegeneration and Repair, Department of Genetics, Yale School of Medicine, New Haven, United States.
authors: Tiffany W
authors: TW
authors: Todd
authors: Program in Cellular Neuroscience, Neurodegeneration and Repair, Department of Genetics, Yale School of Medicine, New Haven, United States.
authors: Hiroshi
authors: H
authors: Kokubu
authors: 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.
authors: Helen C
authors: HC
authors: Miranda
authors: 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.
authors: Constanza J
authors: CJ
authors: Cortes
authors: 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.
authors: Albert R
authors: AR
authors: La Spada
authors: Program in Cellular Neuroscience, Neurodegeneration and Repair, Department of Genetics, Yale School of Medicine, New Haven, United States.
authors: Janghoo
authors: J
authors: Lim
mesh_terms: D000818:Animals; D002460:Cell Line; D004330:Drosophila; D006651:Histocytochemistry; D006801:Humans; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009132:Muscles / Q000473:pathology; D020966:Muscular Disorders, Atrophic / Q000473:pathology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases; D011944:Receptors, Androgen / Q000378:metabolism*; D013116:Spinal Cord / Q000473:pathology; D016019:Survival Analysis
chemical_list: D011944:Receptors, Androgen; C408347:Nlk protein, mouse; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases
keywords: drosophila; mouse; nemo-like kinase; neuromuscular disease; neuroscience; polyglutamine disease; spinal and bulbar muscular atrophy