Intermediate Filaments Associate with Aggresome-like Structures in ProteostressedC. elegansNeurons and Influence the Rate of Large Vesicle Extrusions as Exophers

AbstractIn human neurodegenerative diseases, toxic protein aggregates can spread between neurons to promote pathology. In the transparent animal modelC. elegans, stressed neurons can concentrate fluorescently tagged protein aggregates and organelles and extrude them in large membrane-bound vesicles called exophers, which enter neighboring cells.C. elegansexophergenesis may occur by mechanisms analogous to those that enable aggregate spreading in the human brain in neurodegenerative disease. Here we report on aggresome-like biology in stressedC. elegansneurons that influences exophergenesis. We show thatC. elegansintermediate filament proteins IFD-1 and IFD-2 can assemble into juxtanuclear structures with molecular and cellular characteristics similar to mammalian aggresomes and document that these intermediate filaments are required cell autonomously for efficient exopher production. IFD-concentrating structures expand with age or neuronal stress level, can associate with neurotoxic polyglutamine expansion protein HttQ74, and depend upon orthologs of mammalian adapter proteins, dynein motors, and microtubule integrity for aggregate collection into juxtanuclear compartments. IFD homolog human neurofilament light chain hNFL can partially substitute forC. elegansIFD-2 proteins in promoting exopher production, indicating conservation of the capacity of intermediate filaments to influence large neuronal extrusions. In sum, we identify an unexpected requirement for specific intermediate filaments (counterparts of human biomarkers of neuronal injury and disease, and major components of Parkinson’s disease Lewy bodies) in large vesicle extrusion from stressed neurons.