Molecular Analysis of TorsinA Function and Dysfunction

Emory University, Atlanta GA

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Abstract

? DESCRIPTION (provided by applicant): Dystonia is the third most common movement disorder, ranked after Parkinson disease and tremor. The pathogenic mechanisms underlying dystonia remain poorly understood, and currently there are no curative treatment for this disorder. The identification of a mutation in torsinA as the cause of early-onset generalized torsion dystonia (DYT1) opens up a new avenue for investigating molecular mechanisms that trigger dystonia. In addition, genetic association studies have implicated polymorphisms in the torsinA gene as a risk factor for development of adult-onset idiopathic dystonia. Despite increasing genetic evidence linking torsinA to DYT1 and sporadic dystonia, the function of torsinA is unclear and the pathogenic mechanism of torsinA mutation remains elusive. DYT1 is an autosomal dominant disease with a 30-40% penetrance, suggesting the involvement of yet-unidentified torsinA modifier(s) in DYT1 pathogenesis. To gain insights into torsinA function, we performed an unbiased search for torsinA- interacting proteins in the brain and identified a novel protein that we named printor (protein interactor of torsinA). Printor belongs to the BTB-BACK-Kelch (BBK) protein family whose members have been linked to several human diseases, including giant axonal neuropathy, retinopathy, and distal myopathy. We found that torsinA and printor interact and colocalize in the endoplasmic reticulum (ER) and this interaction/colocalization is disrupted by dystonia-causing torsinA mutation. In this project, we will follow up on our intriguing preliminary results and perform a series of biochemical, cell biological, mouse genetic and functional analyses to elucidate the role of the torsinA-printor complex in normal physiology and dystonia pathogenesis. This research will advance our understanding of DYT1 pathogenic mechanisms and may point to new therapeutic strategies for the treatment of dystonia.