Dystonia 16 (DYT16) mutations in PACT cause dysregulated PKR activation and eIF2 α signaling leading to a compromised stress response.

In this study we evaluate if five DYT16 substitution mutations alter PKR activation and ISR. Our results indicate that the mutant DYT16 proteins show stronger PACT-PACT interactions and enhanced PKR activation. In DYT16 patient derived lymphoblasts the enhanced PACT-PKR interactions and heightened PKR activation leads to a dysregulation of ISR and increased apoptosis. More importantly, this enhanced sensitivity to ER stress can be rescued by luteolin, which disrupts PACT-PKR interactions. Our results not only demonstrate the impact of DYT16 mutations on regulation of ISR and DYT16 etiology but indicate that therapeutic interventions could be possible after a further evaluation of such strategies.
PMID: 33049316 [PubMed - as supplied by publisher]

Source: Neurobiology of Disease - October 10, 2020 Category: Neurology Authors: Burnett SB, Vaughn LS, Sharma N, Kulkarni R, Patel RC Tags: Neurobiol Dis Source Type: research