11/09/2023
By Irma Silva

The Kennedy College of Sciences, Department of Biological Sciences, invites to you attend a Master’s Thesis defense by Lauren Cuoco entitled "An investigation into the use of mutagenesis to identify second site suppressor mutations that rescue aberrant autophagic cargo degradation in Huntington knock out cells using the model organism Dictyostelium discoideum.”

Degree: Master’s
Date: Monday, Nov. 20, 2023
Time: 11 a.m. to 2 p.m.
Location: Olsen 403.For virtual, please contact Lauren_Cuoco@student.uml.edu to obtain link.

Committee Members:

  • Jeffrey Moore, Biological Sciences, University of Massachusetts Lowell
  • Frederic Chain, Biological Sciences, University of Massachusetts Lowell
  • Peter Gaines, Biological Sciences, University of Massachusetts Lowell
  • Michael Fannon, Biological Sciences, University of Massachusetts Lowell

Abstract:
Huntington’s disease (HD) is a neurodegenerative disorder that currently has no effective treatments or cures. Those affected with the disease suffer from loss of bodily control over time, eventually resulting in death about 15 years after disease onset. Huntington’s disease causes multiple aberrations on many pathways in the body, but the focus of this work is specifically aberrations in autophagy caused by the loss of the normal function of the huntingtin gene.

It is known that autophagy is aberrant in huntingtins disease. However, despite decades of research on huntingtin showing its involvement in varying pathways, little is known about the underlying molecular mechanisms driving functional alterations associated with HD, including how HTT acts to sequester cargos to assist in the autophagy pathway.
Research into the normal function of HTT, as proposed here, is essential to determine the molecular processes disrupted by mutant HTT and to indicate targets for HD treatments. A persistent limitation for HTT research is the absence of a viable Murine Htt- model, as deletion of Htt in mice is embryonic lethal. Fortunately, Htt is highly conserved across eukaryotes and the model organism Dictyostelium remains viable without the HTT protein in both its single cell and multicellular fruiting body state. Dictyostelium discoideum Htt has 42% sequence identity with human Htt, and its haploid genome allows ease and tractability of studying the effects of gene knockouts and mutations. Here we will use Htt nulls generated in our lab in the model organism Dictyostelium discoideum to study huntingtin protein function, and in particular its role in autophagy. Dictyostelium cells are an established model system for the study of autophagy because they die naturally through the autophagic process. Dictyostelium cells respond to the same autophagy perturbators as neurons, allowing us to reflect similarities to the neuronal autophagy defect in a readily inducible and well understood model. We hypothesize that knocking out the huntingtin protein results in inhibition of the autophagic response and amino acid homeostasis due to inefficient cargo degradation.