Eukaryotic Initiation Factor 2a Signaling in Dystonia Pathogenesis and Treatment

Duke University, Durham NC

Investigators

Linked publications & trials

Abstract

ABSTRACT Dystonia, a debilitating movement disorder characterized by sustained and painful involuntary postures, is the 3rd most common movement disorder yet very little is known about its biological cause. Currently, only symptomatic treatments are available, which have limited efficacy, significant side effects, and are often invasive or require access to specialized facilities. Early-onset torsion dystonia (DYT1), the most common inherited form of dystonia, is a severe, childhood-onset form of the disease. Recently, our lab conducted a whole-genome RNAi screen using a novel assay of DYT1 cellular pathology, which identified Eukaryotic lnitiation Factor 2? (elF2?) signaling as the most highly enriched pathway. ln subsequent experiments, our lab showed that a compound which enhances elF2? signaling improved the DYT1 cellular pathology and a compound which inhibits elF2? signaling worsened the pathology in a dose-dependent manner, indicating that enhancing elF2? signaling is protective against DYT1 and vice versa. DYT1-isogenic model mice are deficient in a synaptic process known to require elF2? signaling and fibroblast cells derived from DYT1 patients display decreased elF2? signaling in response to stress stimulation, suggesting that elF2? signaling is deficient in DYT1 in vivo. Furthermore, mutations in both an upstream activator and a downstream effector of elF2? signaling are found in patients with other forms of dystonia, suggesting that defective elF2? signaling is critical in non-DYT1 dystonia pathogenesis as well. Therefore, l hypothesize that deficient elF2? signaling is a critical mediator of dystonia pathogenesis and that pharmacologically enhancing elF2? signaling will have therapeutic effects in animal models of dystonia. Here l propose to: 1) Determine how elF2? signaling is disrupted in DYT1 by a) measuring neuronal elF2? signaling in wild type and DYT1 model mice and b) determining how the DYT1-causative mutation leads to deficient elF2? signaling. 2) Determine if enhancing elF2? signaling reverses a synaptic plasticity deficit in DYT1 model mice using slice electrophysiology. 3) Determine if inhibiting elF2? signaling is sufficient to cause dystonic phenotypes in wild-type mice, either alone or in conjunction with environmental stress.