Interactions of Hsp23, FoxO, and ESCRTIII-Vps24 in Mediating Proteostasis in Drosophila melanogaster Flight Motor Cells

Open Access
Fatima, Shahroz
Area of Honors:
Bachelor of Science
Document Type:
Thesis Supervisors:
  • Fumiko Kawasaki, Thesis Supervisor
  • Katriona Shea, Honors Advisor
  • Drosophila melanogaster
  • neurodegeneration
  • proteostasis
  • heat shock
  • Hsp23
  • FoxO
  • Vps24
  • autophagy
  • proteasome
Understanding the molecular mechanisms of cell degeneration, which cause degenerative diseases such as Parkinson's and Alzheimer's, is a key objective in biology and medicine. This complex biological process results from interactions between genetic and environmental factors. We examine these mechanisms using powerful genetic approaches and a newly developed experimental model for stress-induced degeneration in the fruit fly, Drosophila melanogaster. Our project focuses on the cellular and molecular mechanisms mediating neuromuscular degeneration induced by environmental stress, which activates the heat-shock response (HSR) in order to maintain quality control of cellular proteins (proteostasis). We examine the flight motor system of Drosophila melanogaster, which has shown selective susceptibility of neuronal, glial, and muscle cells to increased temperatures. Our previous research showed an upregulation of one particular chaperone protein, Heat-shock protein 23 (Hsp23), during the HSR response. Additionally, an overexpression of Hsp23 in fly muscle cells was shown to protect muscle and have a non-autonomous protective effect on neurons and glia. Moreover, these muscle cells also showed perinuclear localization of ubiquitinated proteins, which are normally targeted for degradation, and thus reveal a unique aspect of proteostasis. Our current research expands on these findings by exploring potential pathways that lead to cell non-autonomous protection from HS stress, focusing on the FoxO transcription factor, which has been implicated in proteostasis and protection from aging. Furthermore, we take a closer look at patterns of ubiquitination to determine whether proteostasis mechanisms involving clearance of misfolded proteins responsible for cell degeneration are carried out by the proteasome or by selective autophagy as related to the ESCRT III complex. We hope our findings will shed light onto the complex and elusive mechanisms responsible for environmental stress-induced degeneration. Moreover, we hope these findings can be applied to the development of treatments and gene-targeted therapies that ease the pain of those suffering from degenerative diseases.