The formation of neuronal inclusions is one of the hallmarks of neurodegenerative diseases. These structures are composed of aggregated proteins, molecular chaperones, and components of the ubiquitin-proteasome system (UPS). Co-localization of aggregated proteins with cell-homeostasis maintaining machinery indicates that the cell may be failing in an attempt to clear these aggregates. Here I explore possible mechanisms of proteasome inhibition in two neurodegenerative disorders, Parkinson's Disease (PD) and Huntington's Disease (HD). These studies were conducted using in vitro proteasome degradation assays with radioactive substrates. I have found that the proteasome inhibition that is seen in PD may stem from its inability to recognize ubiquitinated substrates. I show that the degradation of a substrate is inhibited by the addition of aggregated alpha-synuclein, a protein that is a major component of PD neuronal inclusions. Aggregated alpha-synuclein has high binding affinity for the subunit of the proteasome that is responsible for recognition of substrates targeted for degradation. Taken together, these results suggest that inhibition of degradation in PD is due to the blockage of substrate recognition by binding of aggregated alpha-synuclein to the proteasome. The mechanism of proteasome inhibition in HD may be due to the combination of two effects, processing and inefficient initiation of degradation. A mutation in huntingtin (htt) protein, that causes massive expansion if its polyglutamine tract, is the calling card of HD. This expansion makes the protein highly prone to aggregation. I show that the inability of the proteasome to dispose htt before it reaches aggregate state may be partially mediated inhibition of proteasome progression. My results show that the proteasome cannot efficiently degrade polyglutamine proteins when in the context of a stable protein, but can proceed with ease when associated with a less stable protein domain. Taken together, this suggests that certain structural components of htt may impede progression of degradation, thereby causing the protein to be processed instead of degraded. I also show that mutant

Last modified

• 05/07/2018

Creator

• Kwame Nyanten Mensah

DOI

• https://doi.org/10.21985/N2XM6C

Subject

• Biology

Keyword

• Biology

Date created

• 2006-11-30

Resource type

• Dissertation

Rights statement

• In Copyright