Supplement: Pathophysiology of DYT1 dystonia: Targeted Mouse Models

University Of Florida, Gainesville FL

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Abstract

This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-RM- 24-013. Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements or postures. DYT1 early-onset generalized dystonia is the most common type among genetic dystonias. Most of the individuals affected by DYT1 dystonia share a trinucleotide deletion (ΔGAG) located in exon 5 of DYT1 or TOR1A gene, leading to a loss of a glutamate amino acid residue for torsinA (torsinA∆E). The symptoms start in the limbs and then become generalized. Affected individuals could be seriously disabled and need to use a wheelchair. Conditional knockout of torsinA and knockin of mutant torsinA in mice points to the involvement of multiple brain regions and cell types in the pathogenesis of DYT1 dystonia. So far, these and other pathophysiological studies of DYT1 and other dystonias support a circuit or network model of dystonia pathogenesis. However, which brain region and neuronal types play a critical role in pathogenesis is unclear. Preliminary studies of conditional knockin (KI) mouse models of DYT1 dystonia revealed striatal medium spiny neurons (MSNs) play a vital role in the pathogenesis of DYT1 dystonia. However, how torsinA∆E in MSNs leads to dystonia is unknown. These unknowns impede the development of effective treatment for DYT1 patients. The broad, long-term objective is 1) to determine the functional role of torsinA in vivo and the mechanism by which torsinA∆E leads to DYT1 dystonia, 2) to develop a novel and effective treatment. The specific goal of this supplement application is to replicate the behavioral analysis of a newly developed, targeted DYT1 mouse model with an overt dystonia phenotype without growth retardation and use this model to test its suitability for preclinical drug development (part of the original Aim 1). We hypothesize that additional ΔGAG expression in the striatal MSNs in Dyt1 KI mice will accelerate the development of the dystonia phenotype in mice and better recapitulate the phenotype of human dystonia for pathophysiological studies and preclinical drug testing. We plan to collaborate with NIH-assigned CRO to replicate the newly developed novel overt dystonia model. We will generate and characterize this conditional KI line in the heterozygous Dyt1 ΔGAG KI background. We will perform the tail suspension test to determine the overt dystonia phenotype and the treatment effect of trihexyphenidyl, an FDA-approved drug for dystonia patients. We are particularly well prepared to undertake the proposed research because we have developed and characterized the novel Dyt1 conditional KI mice. The successful completion of the proposed study will characterize and validate a novel DYT1 dystonia mouse model that will contribute significantly to the study of the pathophysiology of DYT1 dystonia and the development of anti-dystonia drug treatment. It will also have an impact on other dystonias and related neurological disorders.