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

Tiffany W Todd,Hiroshi Kokubu,Albert R La Spada,Helen C Miranda,Janghoo Lim,Constanza J Cortes

doi:10.7554/elife.08493

Tiffany W Todd, Hiroshi Kokubu + Show 4 more

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https://doi.org/10.7554/elife.08493

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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.

Highlights

Spinal and bulbar muscular atrophy (SBMA; MIM #313200) is an X-linked progressive neuromuscular disease (Kennedy et al, 1968)
Since SBMA is caused by polyQ-expanded androgen receptor (AR) (La Spada et al, 1991), and polyQ expansion can alter the ability of AR to interact with its binding partners (Hsiao et al, 1999; Irvine et al, 2000; Sopher et al, 2004), we tested if Nemo-like kinase (NLK) could bind mutant AR
We explored whether and how NLK could modulate the pathogenesis of SBMA

Summary

Introduction

Spinal and bulbar muscular atrophy (SBMA; MIM #313200) is an X-linked progressive neuromuscular disease (Kennedy et al, 1968). Patients present in midlife with weakness of the limb and facial muscles, the latter of which often progress to dysarthria and dysphagia, occasionally leading to fatality. SBMA was originally defined as a neurodegenerative disease affecting the proximal spinal and bulbar motoneurons, and muscle atrophy was considered secondary to motoneuron degeneration. Current opinion in the field of SBMA research, favors a model in which SBMA directly affects the skeletal muscles (Yu et al, 2006; Jordan and Lieberman, 2008; Monks et al, 2008; Boyer et al, 2013; Malena et al, 2013; Oki et al, 2015), and, recent studies have shown that removing or decreasing the expression of the mutant protein within skeletal muscle is sufficient to rescue SBMA phenotypes in vivo (Cortes et al, 2014; Lieberman et al, 2014). This model of disease is supported by the finding that, in conjunction with neuronal loss, patients show elevated creatine kinase levels and evidence of myopathic changes on biopsy (Soraruet al., 2008; Chahin and Sorenson, 2009)

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