Protein quality control, Aggregation, ERAD, Nuclear PQC
Cells need proteins to carry out molecular functions, but proteins can become damaged or misfolded, which inhibits their function and can cause aggregation. Misfolded protein aggregation is associated with degenerative diseases in mammals. In Eukaryotic cells, chronically misfolded proteins can be destroyed by the Ubiquitin Proteasome System (UPS) as a way to prevent aggregation and disease. For my thesis work, I have investigated two pathways that participate in the UPS.
First, I investigate Endoplasmic Reticulum Associated Degradation (ERAD), a UPS pathway is active in the Endoplasmic Reticulum (ER) of eukaryotic cells. ERAD is well characterized in Saccharomyces cerevisiae (yeast), but has only recently been studied in multicellular systems. The Dahlberg Lab has begun to characterize the ERAD pathway regulating GLR-1, a glutamate receptor in the neurons of Caenorhabditis elegans. GLR-1 is a substrate for the E3 Ubiquitin ligase HRDL-1 in ERAD, and it accumulates in the cell when HRDL-1 is non-functional. We characterize location of accumulating GLR-1 in the absence of HRDL-1 with organelle level resolution. By determining the glycosylated state of GLR-1, we find that additional GLR-1 remains in the ER when HRDL-1 is nonfunctional. Our finding suggests that GLR-1 is likely accumulating in a misfolded state when ERAD is impaired.
Second, we begin to characterize another branch of the UPS that acts in the nucleus of Eukaryotic cells. A nuclear UPS pathway has also been investigated in S. cerevisiae, but a homologous pathway in a multicellular system has not been characterized. Using C. elegans, we demonstrate that aggregation prone proteins accumulate in the nuclei of body wall muscle cells, and that nuclear accumulation increases between the second and third day of the worm’s life.
Studying protein quality control in C. elegans can help us understand how it might function more generally in metazoan systems. Human diseases involving protein aggregation, such as Parkinson’s, Alzheimer’s, Huntington’s, and other neurodegenerative diseases, highlight the importance of protein quality control mechanisms in metazoan systems. Learning about protein quality control in a C. elegans may help us understand protein aggregation diseases in humans.
Hassell, Daniel, "Protein Quality Control at the Endoplasmic Reticulum and Nucleus in Caenorhabditis elegans" (2019). WWU Honors Program Senior Projects. 113.
Subjects - Topical (LCSH)
Ubiquitin; Ligases; Biotransformation (Metabolism); Proteins--Metabolism; Endoplasmic reticulum; Caenorhabditis elegans
student projects; term papers
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