Exploring Protein Quality Control Dysfunction in Dystonia
Abstract
During the first year of this award, we made excellent progress towards defining cellular and molecular defects implicated in the congenital disorder DYT1 dystonia, the most severe form of dystonia that is characterized by spasms, twisted postures and involuntary muscle contractions. Starting from a tissue culture-based model, we identified the molecular signature of nuclear envelope abnormalities that are characteristic for many animal-based disease models of DYT1 dystonia. In doing so we defined robust biomarkers that are of immediate diagnostic utility for several forms of dystonia affecting veterans. In addition, we functionally investigated these molecules leading to the discovery of novel enzymatic activities that govern nuclear pore complex assembly which is perturbed in the disease state. Lastly, we developed novel methodology to show that nuclear envelope defects in dystonia profoundly perturb the cellular protein quality control system, critically informing the development of novel therapeutic avenues.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2022
- Accession Number
- AD1190995
Entities
People
- Christian Schlieker
Organizations
- Yale University