Abstract

Toxicity of misfolded proteins and mitochondrial dysfunction are key factors that promote age-associated functional neuronal decline and neurodegenerative disease across species. Although these neurotoxic challenges have long been considered to be cell-intrinsic, evidence now supports that misfolded human disease proteins originating in one neuron can be transferred to neighboring cells, a phenomenon proposed to promote pathology spread. Likewise, mitochondria can be sent out of the cell that made them for transcellular degradation by neighbors. We discovered and are characterizing a dramatic, but previously unknown, capacity of C. elegans adult neurons to extrude large (~5µM) vesicles that can include aggregated proteins (including human neurodegenerative disease proteins) and damaged mitochondria. Strikingly, extruded exopher contents can be found in both neighboring and remote cells. 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 neurodegenerative disease. I will present our current understanding of how trash is identified, sorted, transported, packaged for specific elimination, and reacted to by neighboring cells.