Combating 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's diseases.
We discovered a novel capacity of young adult C. elegans neurons - neurons can extrude substantial packets of cellular contents, which can include aggregated human neurodegenerative disease proteins, mitochondria, or lysosomes, but no nuclear DNA. We currently call these extrusions "exophers". The ability to jettison cell contents appears to change with age, and extrusion is increased when protein turnover is impaired, autophagy is inhibited, or mitochondria are compromised. Moreover, exophers can selectively incorporate aggregation-prone proteins and mitochondria with elevated levels of an oxidized reporter. Thus, exopher-mediated extrusion may constitute a novel neuronal protection mechanism that serves to maintain protein/organelle homeostasis when other systems are compromised or overloaded. We 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 neurodegenerative diseases, this pathway may malfunction to promote spread of pathology. We will present the basic characterization of neuronal exopher production and our latest data on genetic influences on exopher generation.
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