Dysregulation of the PACT-Mediated Crosstalk Between Protein Kinases PKR and PERK Contributes to Dystonia 16 (DYT16)
Technical Report,01 Apr 2018,31 Mar 2019
University of South Carolina Columbia United States
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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.
- Medicine and Medical Research