Uncovering the Contribution of Cell-Type-Specific ER Proteostasis Networks to PD Pathogenesis
Abstract
Parkinson s disease (PD) is the second most common neurodegenerative disorder, resulting in impaired motor control caused in part by the loss of dopaminergic neurons at the Substantia Nigra pars compacta (SNpc). Veterans and deployed military exposed to hazardous chemicals are considered to suffer symptoms related to PD. The primary mechanism responsible for the progressive neuron loss in PD remains unknown. Clues have been obtained from families with sporadic and familial PD, which are accompanied by alterations in the folding of important proteins including alpha synuclein, among other factors. Perturbations of the protein-folding functions performed at a subcellular organelle called the endoplasmic reticulum (ER) have been extensively suggested as a common factor driving brain dysfunction in PD. We have obtained data supporting the efficacy of a gene therapy strategy to provide neuroprotection against experimental PD triggered by neurotoxins, environmental factors known to trigger PD. In this project, we aim to develop a systematic approach and define for the first time the relative contribution of protein homeostasis in the interplay between different cell types of the brain in PD. This work will set the basis to the design of novel therapeutic strategies to treat this PD. This project represents a unique opportunity to evaluate new concepts to target the proteostasis network of the brain in PD as a tool to ameliorate the pathology; a novel idea that we hope will be useful to develop future treatments for this neurodegenerative disease. We expect that the results obtained in this proposal will have an impact to improve the quality of life of Veterans and the general population of patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110960
Entities
People
- Claudio Hetz
Organizations
- United States Army