Dysregulation of the PACT-Mediated Crosstalk Between Protein Kinases PKR and PERK Contributes to Dystonia 16 (DYT16)
Abstract
Topic Area: Dystonia. One of the reasons for a lack of effective drug therapies for dystonia has been a poor understanding of the molecular pathways affected in patients. Our proposed project is aimed at understanding the pathomechanism involved in dystonia 16 (DYT16). DYT16 is caused by mutations in the gene PACT (also known as PRKRA). DYT16 patients show an early onset of the disease, mostly in limbs during childhood, then progressing with age to other parts of the body. The first PACT mutation leading to DYT16 was described in 2008, and the list of mutations in PACT leading to DYT16 has now grown to seven different mutations in a worldwide occurrence. PACT is involved in eIF2 alpha signaling pathway via activation of PKR protein kinase, which regulates survival or death decisions in response to endoplasmic reticulum stress. Endoplasmic reticulum is a membranous structure within the cells where proteins are synthesized. Any perturbations in endoplasmic reticulum affect the overall functioning of the cell and are thus sensed as “endoplasmic reticulum stress.” A myriad of environmental signals lead to endoplasmic reticulum stress in brain and other organs during the course of normal life. PERK is the main protein that is activated in response to endoplasmic reticulum stress and turns the eIF2 alpha signaling pathway on. It is currently unknown how mutations in PACT that cause DYT16 affect PERK activity leading to downstream signaling to PKR and eIF2 alpha in this pathway. We will investigate the effect of DYT16 mutations on the biochemical activity PERK and the regulatory crosstalk between PERK and PKR pathways. Our proposal centers on examining if the PERK-eIF2 alpha signaling pathway is functioning optimally in the presence of DYT16 mutant forms of PACT protein. The proposed research is innovative as the effect of PACT mutations on PERK has never been examined prior to this. We propose to explore the presence of a novel branch of the eIF2 alpha signaling pathway and to test the effect of PACT mutations on resolution of endoplasmic reticulum stress by restoring cellular homeostasis. The results are expected to discover a previously unknown branch of this signaling pathway and add significant new knowledge to both basic research and drug development. Successful completion of our proposed research will, for the first time, present dystonia researchers with a unifying mechanism that is applicable to several inherited forms of dystonia as well as injury-induced, late-onset dystonia. In addition, these studies will provide very helpful information for development of novel drugs that may be used to alleviate movement disorder in multiple forms of dystonia. The proposed research will thus add a completely new paradigm for basic understanding of how cells respond to endoplasmic reticulum stress signals and help translational research by identifying novel drug targets.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810088
Entities
People
- Rekha C Patel
Organizations
- United States Army
- University of South Carolina