Elias Aizenman, PhD (PI)
Department of Neurobiology
Michael Palladino, PhD (co-PI)
Pharmacology and Chemical Biology
University of Pittsburgh
Genetic Programming of a Neuroprotective Pathway in Fly Models of Neurodegeneration
Abstract: There are currently no known therapies to prevent or halt neuronal cell death in neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease or Amyotrophic Lateral Sclerosis (ALS). Although several mechanisms have been proposed to account for the demise of neurons in both sporadic and inherited forms of these disorders, the fact remains that we do not specifically know how or when any given neuron or group of neurons (brain cells) will die in the course of these diseases. In this proposal, we present a transformative new idea that addresses these very issues, based on our extensive previous data identifying a seemingly ubiquitous signaling cascade that is activated following lethal injury to initiate the process of neuronal cell death. Using molecular techniques in fruit fly (Drosophila) models of human neurodegenerative diseases, we will deliver a silent gene that will be activated by the metal zinc, which is liberated inside neurons during a lethal injurious stimulus. This normally silent gene will only be activated during injury, and its product is designed to block the final stages of a signaling mechanism that leads to the loss of intracellular potassium, a requisite step for cell death to occur. Results from this work are of potential high significance and could be transformative and highly impactful, as they not only address a critical scientific problem of high relevance to human disease, but also may provide a technological breakthrough to surmount a critical barrier in the field.