Toxicity of misfolded proteins and mitochondrial dysfunction are pivotal factors that promote age-associated functional neuronal decline and neurodegenerative disease. Accordingly, neurons invest considerable cellular resources in chaperones, protein degradation, autophagy, and mitophagy to maintain proteostasis and energy/redox balance while avoiding neurotoxicity. Although these neurotoxic challenges have long been considered to be cell-intrinsic, evidence now supports that both misfolded human disease proteins and mitochondria originating in one neuron can appear in neighboring cells, a phenomenon proposed to promote pathology spread. We have discovered and characterized a previously unknown capacity of C. elegans adult neurons to extrude large (~5µM) vesicles that include substantial amounts of cytoplasmic contents via a dynamic process requiring specific cytoskeletal proteins and motors. These “exopher” vesicles can include fluorescent GFP or mCherry, loaded DiI, aggregated human proteins such as an expanded Q128 polyglutamine protein, lysosomes, and/or mitochondria. Aggregated protein and oxidized mitochondria can be preferentially segregated into exophers, and neurons that extrude exophers generally function better than those that do not. Inhibiting chaperone expression or autophagy, as well as compromising mitochondrial quality, enhances exopher prevalence, revealing exopher-genesis as a response to stresses in proteostasis and organelle maintenance. Strikingly, extruded exopher contents can be found in both neighboring and remote cells, and thus exophers can contribute to a neuronal “contagion” mechanism. We suggest that “throwing out the trash” is a conserved mechanism that constitutes a fundamental, but formerly unrecognized, branch of neuronal proteostasis and mitochondrial quality control, which, when imbalanced, might actively contribute to the spread of neurotoxic species relevant to pathogenesis in human neurodegenerative disease and may be a factor in neuronal aging.
Dr. Driscoll is a Professor in the Graduate Programs in Molecular Biosciences at Rutgers University.
Audience: Scientific and Medical Community.