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 gene mutated 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 is a substrate of PERK kinase and PERK phosphorylates PACT in vivo after ER stress. 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 now been conclusively shown to be a dysregulation of eIF2 alpha signaling. Thus, our research has uncovered a PACT-mediated novel regulatory pathway and laid the foundation for more in depth drug development to target PACT-PERKinteractions in future. In addition, it has added significant new knowledge about how cells respond to ER stress. In the brief period of 8 months we made significant progress included in this report, before the COVID-19 pandemic slowed down our work significantly.