Date of Graduation
School of Medicine
David M. Smith
Proteostasis is maintained by several systems in the cell including the ubiquitin-proteasome system (UPS), chaperones, chaperone-mediated autophagy, and macroautophagy. The UPS is the principle route for the degradation of intracellular misfolded, damaged, or unneeded cellular proteins and has a critical role essential every cell process, including: cell cycle progression, transcriptional regulation, genome integrity, apoptosis, immune responses, and neuronal plasticity. When the efficiency of protein degradation is perturbed, misfolded and damaged protein aggregates can accumulate to toxic levels and cause neuronal dysfunction, which may underlie many neurodegenerative diseases. It is widely appreciated that soluble oligomers of misfolded proteins (e.g. Aβ, Alzheimer’s; α-Syn, Parkinson’s; huntingtin with polyglutamine expansion, Huntington’s) and loss of proteostasis are the key drivers of disease development and progression. We show that three different proteins from Alzheimer’s, Parkinson’s, and Huntington’s disease that misfold and oligomerize into a shared three-dimensional structure potently impair the proteasome. Detailed mechanistic analysis demonstrates that these oligomers inhibit the 20S proteasome through allosteric impairment of the substrate-gate. To investigate the feasibility of proteasome gate-activation as a therapeutic strategy, we characterized the mechanism of proteasome gate activation by the conserved HbYX-motif found in proteasome activator complexes at the molecular level. Based on these observations, we developed a novel proteasome gate-activating molecule as a research tool to probe proteasome function in vitro and in vivo. Together, our results provide a novel molecular model for oligomer-driven proteasome impairment in neurodegenerative disease and demonstrate the feasibility of designing drug-like molecules that activate proteasome function patients with neurodegenerative disease.
Thibaudeau, Tiffany Ann, "Elucidating a Common Mechanism of Proteasome Impairment in Neurodegenerative Disease and its Pharmacological Intervention" (2019). Graduate Theses, Dissertations, and Problem Reports. 3780.