Nemo-like kinase is a novel regulator of spinal and bulbar muscular atrophy
- Yale School of Medicine, United States
- University of California, San Diego, United States
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. Here 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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Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#2013-11342) of the Yale University. The Yale University Institutional Animal Care and Use Committee approved all research and animal care procedures. We made every effort to minimize animal suffering.
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© 2015, Todd et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Nemo-like kinase is a novel regulator of spinal and bulbar muscular atrophy
eLife 4:e08493.
https://doi.org/10.7554/eLife.08493
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