Using yeast to find therapies for the neurological disease Early-Onset Torsion Dystonia

LUCIA F. ZACCHI; MICHAEL J. MIHALEVIC; JONAS HONER; KATIE M. NIEMEYER; JOHN C. DITTMAR; ANNETTE M. SHEWAN; BENJAMIN L. SCHULZ; KARA A. BERNSTEIN; JEFFREY L. BRODSKY

BRISBANE

Simposio; Brisbane Cell and Developmental Biology Meeting; 2015

Australian Cell Biology Society

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-OnsetTorsion Dystonia (EOTD). EOTD is associated with the deletion of one glutamate residue(deltaE) near the C-terminus of torsinA. TorsinA belongs to the only known family of AAA+ ATPases that resides within the endoplasmic reticulum (ER), where itmay participate in ER quality control. The precise function of torsinA and the reasons torsinAΔE lead to EOTD are unclear. The lack of understanding of the molecular mechanisms of disease has complicated the rational design of therapies to treat this disorder.We are implementing a different approach to identify therapeutic targets for EOTD.Our approach does not focus on fixing the cellular processes affected by the deltaE mutation but rather on preventing the deltaE effects from occurring. Our goal is tohelp the cell eliminate torsinAdeltaE from the ER, leaving only torsinA. We hypothesize that by identifying genetic components that impact the folding and degradation of torsinAdeltaE we will uncover therapeutic targets for EOTD. To this end, we are employing a targeted approach (in which we test specific factors of interest) and a genome-wide,unbiased approach, using the model organism Saccharomyces cerevisiae as an expression system. Through our targeted approach we identified several ER chaperones that are required for the folding and/or stability of torsinAdeltaE both in yeast and mammalian cells, including the ER Hsp70 BiP and the protein disulfide isomerase PDI. Through our genome-wide approach we identified ~250 genes that impact torsinAdeltaE stability, and a significant proportion of these genes are involved in protein glycosylation. Glycosylation is a posttranslational modification that impacts protein stability, folding, traffic, oligomerization, and function. Glycans play a key role in brain function and development, and glycosylation defects can lead to severe neurological symptoms and are associated with neurological diseases. Thus, defects in glycosylation may contribute to EOTD, and we are testing this possibility. These findings represent potential pharmacological and/or genetic therapeutic targets for this currently untreatable disease.