Forebrain deletion of the dystonia protein torsinA causes dystonic-like movements and loss of striatal cholinergic neurons.

Samuel S Pappas,Michael S Levine,Jenny-Marie T Wong,Katherine Darr,Sandra M Holley,William T Dauer,Tessa M Lewitt,Reema Paudel,Henry Houlden,Carlos Cepeda,Robert T Kennedy,Omar S Mabrouk

doi:10.7554/elife.08352

Abstract

Striatal dysfunction plays an important role in dystonia, but the striatal cell types that contribute to abnormal movements are poorly defined. We demonstrate that conditional deletion of the DYT1 dystonia protein torsinA in embryonic progenitors of forebrain cholinergic and GABAergic neurons causes dystonic-like twisting movements that emerge during juvenile CNS maturation. The onset of these movements coincides with selective degeneration of dorsal striatal large cholinergic interneurons (LCI), and surviving LCI exhibit morphological, electrophysiological, and connectivity abnormalities. Consistent with the importance of this LCI pathology, murine dystonic-like movements are reduced significantly with an antimuscarinic agent used clinically, and we identify cholinergic abnormalities in postmortem striatal tissue from DYT1 dystonia patients. These findings demonstrate that dorsal LCI have a unique requirement for torsinA function during striatal maturation, and link abnormalities of these cells to dystonic-like movements in an overtly symptomatic animal model.

Highlights

Primary dystonia encompasses a group of sporadic and inherited disorders characterized by disabling involuntary twisting movements
Our results suggest that the selective loss of large cholinergic interneurons (LCI) may be a pathogenic event in DYT1 dystonia
Our studies establish the first model of DYT1 dystonia that exhibits face, construct, and predictive validity

Summary

Introduction

Primary dystonia encompasses a group of sporadic and inherited disorders characterized by disabling involuntary twisting movements. This sole clinical feature of primary dystonia implies selective abnormalities of motor pathways. The absence of an overt neuropathological signature complicates identification of pathogenic brain structures and cell types, and underlies the widely accepted notion that primary dystonia results from abnormal functioning of a structurally intact central nervous system (CNS). Several lines of evidence implicate the striatum as the major node of dysfunction in primary dystonia. Secondary dystonia–where symptoms result from CNS damage or exogenous pharmacological insult–is linked strongly to striatal (especially putaminal) damage (Marsden et al, 1985). Striatal-associated behavioral (Carbon et al, 2011) and functional imaging abnormalities are present

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