6^th International Conference on
Neurology and Neuromuscular Diseases

Rekha Patel has her expertise in the area of PKR regulated cell apoptosis in response to cellular stress. Her research on biochemical and molecular pathways that regulate cellular survival after stress signals has been central to understanding the etiology of dystonia 16 . She has built this model after years of experience in research on PKR regulated signaling pathways. Her work has provided a groundwork to understand the common pathways that are dysfunctional in various forms of dystonias. Her pioneering work has offered a novel paradigm for more investigations in basic molecular pathways in dystonias and also for therapeutic interventions that may work for different dystonias.

Dystonia is an inherited neuromuscular movement disorder that can result from mutations in more than 25 different genes. The patients suffer from inability to control their dystonic, often sustained repetitive movements, and have a compromised posture. One type of primary dystonia, the early onset dystonia 16 (DYT16), has been shown to be result from various mutations in the PACT (also known as PRKRA) gene that has been well characterized for its role in regulating apoptosis in response to cellular stress.
 

Under conditions of viral, oxidative, or endoplasmic reticulum stress, the cellular apoptosis has been shown to be regulated by prolonged translation inhibition resulting from kinase activity targeting the eukaryotic translation initiation factor 2 alpha. Events leading to eIF2 alpha phosphorylation in response to cell stress are attributed to interactions between three double stranded RNA binding proteins: PACT, TRBP, and PKR. These proteins interact with each other forming homo- and heterodimers to impact cellular fate in response to stress signals. PACT is a protein activator of PKR, a serine-threonine kinase involved in innate immunity. PACT-PKR interaction is essential for facilitating apoptosis; whereas, transactivation RNA binding protein (TRBP) serves as a PKR inhibitor via PACT-TRBP and TRBP-PKR heterodimerization. We investigated the altered protein-protein interactions between PACT, PKR, and TRBP resulting from various mutations in DYT16 patients, and for the first time in a mouse model of DYT16. Using various biochemical techniques, we characterized how these mutations influence PACT’s function during stress response to regulate apoptosis. By utilizing DYT16 patient samples as well as an analogous mouse model with dystonia we are attempting to better understand how PACT mutations may lead to early onset dystonia. Our research highlights the insight obtained by applying biochemical, and molecular analysis to patient cells and mouse models to understand the etiology and pathophysiology of dystonia.