Transcellular regulation of the proteostasis network in Kennedy’s disease

Project: Research project

Project Details

Description

Expansion of a polyglutamine-encoding CAG repeat in the androgen receptor (AR) causes Kennedy’s disease (spinal and bulbar muscular atrophy, SBMA), a degenerative disease that is characterized by a progressive loss of lower motor neurons and muscle weakness. Misfolding and abnormal accumulation of the mutant AR in the disease is associated with defects in the protein homeostasis network, which underlies cellular, tissue, and systemic regulation in multicellular organisms. Recent studies have established non-neuronal tissues such as muscle as target of the mutant protein that contribute to motor neuron degeneration in SBMA, however, the molecular basis for cell-nonautonomous pathogenesis remain to be defined. This project aims to investigate the effects of tissue-specific AR expression on the protein homeostasis network in and across the major tissue types in C. elegans. Specifically, we will determine the effects of mutant AR expression on the folding environment in neurons and muscle using genetically encoded folding sensors and tissue-specific transcriptomic analyses. In parallel, we will perform a tissue-specific RNA interference screen targeting muscle to identify genes and pathways that regulate neuronal protein aggregation via cell-nonautononous mechanisms. We expect that the results from our study will increase our understanding of intertissue communication in SBMA and may lead to the identification of new therapeutic targets.
StatusFinished
Effective start/end date12/1/1711/30/18

Funding

  • Kennedy's Disease Association (Letter 11/30/2017)

Fingerprint

Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.