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

eLife

Albert R La Spada¹  Constanza J Cortes¹  Helen C Miranda¹  Tiffany W Todd²  Hiroshi Kokubu²  Janghoo Lim² 

[1] 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;Program in Cellular Neuroscience, Neurodegeneration and Repair, Department of Genetics, Yale School of Medicine, New Haven, United States;

关键词: spinal and bulbar muscular atrophy;    neuromuscular disease;    polyglutamine disease;    nemo-like kinase;   

DOI  :  10.7554/eLife.08493

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown