Proteostasis Dysfunction in Mitochondrial Disease
Abstract
Topic Area: Mitochondrial Disease Model organisms, including the fruit fly Drosophila, represent fast, cheap model systems in which the fundamental causes and consequences of mitochondrial diseases can be investigated and therapies rapidly tested. The current proposal capitalizes on large new dataset derived from powerful screening approaches in fruit flies that provides important and unexpected clues to the basic pathways within the cell that are harmed when mitochondria stop working properly in disease states. Since mitochondria are the energy generators, or “powerhouses,” of the cell, most experimentation and treatment development has focused on how to re-energize the cell when mitochondria stop working. However, although these approaches are important, they have not yet led to a full understanding of the problems that occur within a cell when mitochondria become abnormal. Nor have conventional approaches led to an effective therapy for the devastating effects of mitochondria diseases in patients. The current proposal thus investigates a novel cause for mitochondria disease: abnormal clumping of proteins together into collections that cannot be removed effectively from the cell. Although clearance of old proteins from the cell used to be thought of as a passive process in which proteins that had outlived their usefulness simply fell apart, important scientific discoveries over the past several decades have instead revealed a complicated cellular machinery dedicated to removing these superannuated proteins. Based on insights from a novel set of data, the current proposal investigates the idea that failure to properly remove old proteins starts a cascade that causes neurons within the brain to malfunction and ultimately die in patients with severe mitochondrial diseases. Given the critical need for new treatments for patients with mitochondrial disorders, the proposal further tests the roles of specific types of proteins in the protein breakdown process that have typically been good targets for drugs. In summary, the overall goals of the current proposal are to both demonstrate a new way in which abnormal mitochondria lead to dysfunction and death of neurons and to study in detail the cellular regulators of the process that offer the best chance of developing new therapies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710530
Entities
People
- Mel Feany
Organizations
- United States Army