Accession Number:

AD1167697

Title:

Dysregulation of the PACT-Mediated Crosstalk Between Protein Kinases PKR and PERK Contributes to Dystonia 16 (DYT16)

Descriptive Note:

[Technical Report, Final Report]

Corporate Author:

SOUTH CAROLINA UNIV COLUMBIA

Personal Author(s):

• Patel, Rekha C.
• Burnett, Samuel B.
• Frederick, Kenneth

Report Date:

2022-01-01

Pagination or Media Count:

34

Abstract:

Currently, the available treatment options for dystonia are merely palliative and the drug development has not progressed due to a lack of understanding about the involved molecular pathomechanisms. We investigated if PACT, the gene mutated in dystonia16 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. There were two very significant findings. 1 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 had remained unknown although a dysregulation of eIF2 alpha signaling was reported due to PACT-mediated regulation of PKR. No information was available for PACTs effect on PERK activity. Our research uncovered a PACT-mediated novel regulatory pathway and laid the foundation for in depth drug development to target PERK-PACT-PKR interactions. 2 A plant flavonoid, luteolin, which disrupts the abnormally strong PACTPKR interactions in DYT16 cells restores the maladaptive eIF2 alpha signaling and protects cells. The PACT-PKR-eIF2 alpha signaling pathway is ubiquitous and regulates cell fate universally in all cells. Thus, luteolin can potentially be therapeutic for several other dystonia types with maladaptive eIF2 alpha signaling. An application to investigate this in depth is currently pending for the PRMRP Expansion Award mechanism.

Descriptors:

• health services
• medical personnel
• cell physiological processes
• neurodegeneration
• chemistry
• diseases and disorders
• amino acids
• chemical compounds
• brain
• movement disorders
• alzheimer disease
• proteins
• covid-19
• neurodegenerative diseases
• neutral amino acids
• animal structures
• apoptosis

Subject Categories:

• Medicine and Medical Research

Distribution Statement:

[A, Approved For Public Release]