Finding therapies for Dystonia

LUCIA F ZACCHI

Brisbane

Seminario; Royal Brisbane Women Hospital, Neurology Seminars.; 2016

Royal Brisbane Women Hospital

Dystonia is the third most common movement disorder, but its diagnosis and treatment remain challenging. One of the most severe types of dystonia is Early-Onset Torsion Dystonia (EOTD). The most common EOTD is caused by a mutation in DYT1/TOR1A called DE. DYT1/TOR1Aencodes torsinA, and the EOTD mutant torsinADE causes a number of cellular and biochemical defects.However, it is still unclear how these defects lead to EOTD. The DE mutation is dominant, but it has a low penetrance (~30%), indicating that other unknown genetic and environmental factors play a critical role in disease onset. We reasoned that if we could identify genetic factors affecting torsinA or torsinADE biogenesis or function, we would be able to: 1)better understand disease mechanisms; 2) utilize these factors as therapeutic targets to modulate the cellular levels and stability of torsinA and torsinADE; 3) identify genetic risk factors for EOTD onset;and 4) identify biomarkers for disease diagnosis. With these objectives inmind, we performed a novel systematic screen for genes altering torsinADE expression and identified >250 genes. We are currently validating select hits of interest. Our approach can be employed to study other subtypes of Dystonia and other polygenic diseases associated with dominant low penetrant mutations.