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Characterizing a novel pathway for aggregate/organelle extrusion that maintains neurons
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Melentijevic, Ilija. Characterizing a novel pathway for aggregate/organelle extrusion that maintains neurons. Retrieved from https://doi.org/doi:10.7282/t3-8dd6-em81

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TitleCharacterizing a novel pathway for aggregate/organelle extrusion that maintains neurons
NameMelentijevic, Ilija (author); Driscoll, Monica (chair); Grant, Barth (member); Rongo, Christopher (member); Cai, Qian (member); Rutgers University; School of Graduate Studies
Date Created2022
Other Date2022-05 (degree)
SubjectMolecular biology, Nervous system -- Degeneration
Extent129 pages : ilustrations
DescriptionCombating late-onset neurodegenerative disease and age-associated functional decline in brain are major health challenges of our time. For the effective design of interventions that protect the nervous system from disease-induced and/or age-associated deterioration, we must fully understand endogenous mechanisms for neuronal protection and how they might fail to enable disease promotion. Recently, it has come to be appreciated that neurodegenerative disease proteins/aggregates can be found outside of mammalian neurons, and when outside can actually be taken up by neighboring cells. Transfer of offending molecules has been suggested to be a mechanism of pathogenesis spread for multiple neurodegenerative diseases, including the prevalent Alzheimer's and Parkinson diseases. I discovered a novel capacity of young adult C. elegans neurons - neurons can extrude substantial packets of cellular contents in membrane surrounded vesicles, which can include aggregated human neurodegenerative disease proteins, mitochondria, or lysosomes, but no nuclear DNA. I named these structures exophers. The ability to jettison cell contents appears to change with age, and extrusion is increased when protein turnover or autophagy is inhibited. Moreover, exophers can selectively incorporate aggregation prone proteins. Thus, the exopher pathway may constitute a novel neuronal protection mechanism that serves to maintain protein/organelle homeostasis when other systems are compromised. I propose that the neuronal extrusion phenomenon constitutes a significant but currently unknown conserved pathway by which healthy neurons maintain their functions, and speculate that, in diseases, this pathway may malfunction to promote spread of pathology. Exopher formation appears to be a highly coordinated process involving molecular motors, cytoskeleton reorganization, quality control proteins, membrane remodeling, and other as-of-yet unknown processes. Since exophers are a new phenomenon, it is likely that many important genes involved in their biogenesis are either undescribed, or have only unrelated roles described. To identify these genes in the powerful C. elegans model, an unbiased screen would be required. I developed a high throughput robotic screening protocol based on RNAi knockdown to identify exopher modifier genes, as well as many other phenotypes in the C. elegans organism. We expect this screen to be productive in elucidating exopher formation mechanisms and yield translationally relevant results.
NotePh.D.
NoteIncludes bibliographical references
Genretheses
Persistent URLhttps://doi.org/doi:10.7282/t3-8dd6-em81
LanguageEnglish
CollectionSchool of Graduate Studies Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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