TorsinB overexpression prevents abnormal twisting in DYT1 dystonia mouse models.

Jay Li,Samuel S Pappas,Chun-Chi Liang,William T Dauer

doi:10.7554/elife.54285

Abstract

Genetic redundancy can be exploited to identify therapeutic targets for inherited disorders. We explored this possibility in DYT1 dystonia, a neurodevelopmental movement disorder caused by a loss-of-function (LOF) mutation in the TOR1A gene encoding torsinA. Prior work demonstrates that torsinA and its paralog torsinB have conserved functions at the nuclear envelope. This work established that low neuronal levels of torsinB dictate the neuronal selective phenotype of nuclear membrane budding. Here, we examined whether torsinB expression levels impact the onset or severity of abnormal movements or neuropathological features in DYT1 mouse models. We demonstrate that torsinB levels bidirectionally regulate these phenotypes. Reducing torsinB levels causes a dose-dependent worsening whereas torsinB overexpression rescues torsinA LOF-mediated abnormal movements and neurodegeneration. These findings identify torsinB as a potent modifier of torsinA LOF phenotypes and suggest that augmentation of torsinB expression may retard or prevent symptom development in DYT1 dystonia.

Highlights

DYT1 dystonia is a dominantly inherited movement disorder that is caused by 3 bp in-frame deletion (DE mutation) in the TOR1A gene that encodes the torsinA protein (Ozelius et al, 1997)
Our findings demonstrate that torsinB is a genetic modifier of torsinA LOF disease-related phenotypes and suggest that enhancing torsinB function may be a viable therapeutic strategy in DYT1 dystonia
Glial fibrillary acidic protein (GFAP) immunohistochemistry did not demonstrate any areas of gliosis (Figure 1—figure supplement 1C)

Summary

Introduction

DYT1 dystonia is a dominantly inherited movement disorder that is caused by 3 bp in-frame deletion (DE mutation) in the TOR1A gene that encodes the torsinA protein (Ozelius et al, 1997). The DYT1 mutation reduces protein stability and impairs interaction with cofactors (LAP1 and LULL1) that appear important for torsinA ATPase activity (Goodchild and Dauer, 2005; Naismith et al, 2009; Zhao et al, 2013). Conditional CNS deletion of both torsinA and torsinB causes NE budding in neuronal and nonneuronal (e.g. glia) cells, and overexpressing torsinB significantly reduces NE budding in torsinA null developing neurons in vitro (Tanabe et al, 2016). Based on these data, we hypothesized that altering torsinB levels would modulate motor and neuropathological phenotypes of DYT1 mouse models. Our findings demonstrate that torsinB is a genetic modifier of torsinA LOF disease-related phenotypes and suggest that enhancing torsinB function may be a viable therapeutic strategy in DYT1 dystonia

Results

Discussion

Materials and methods