Dysregulation of the PACT-Mediated Crosstalk Between Protein Kinases PKR and PERK Contributes to Dystonia 16 (DYT16)
Abstract
Currently, the available treatment options for dystonia are merely palliative and the drug development has not progressed significantly due to a lack of understanding about the involved molecular pathomechanisms. We investigated if PACT, the genemutated in dystonia 16 (DYT16), causes a disruption in the normal regulatory crosstalk between PERK and PKR kinases leading to a loss of cell homeostasis after ER stress. Both PERK and PKR kinases phosphorylate eIF2 alpha and activate a downstream signaling pathway that allows recovery and survival after ER stress. The most significant finding during the last funding period was that PACT serves as a substrate of PERK kinase. This is a paradigm-shifting finding as it was previously unknown that PACT could participate and regulate both PKR and PERK pathways. The molecular etiology of DYT16 has remained unknown although a dysregulation of eIF2 alpha signaling has been suggested due to PACT-mediated regulation of PKR. No information was available for PACTs effect on PERK activity. Thus, our research has uncovered a PACT-mediated novel regulatory pathway and laid the foundation for more in depth drug development to target PACT-PERK interactions in future. In addition, it has added significant new knowledge about how cells respond to ER stress.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2019
- Accession Number
- AD1094976
Entities
People
- Rekha C Patel
- Samuel Burnett
Organizations
- University of South Carolina