Wednesday, June 4, 2025
6/4/2025
Molecular and Cell Biological Foundations of Proteostress-Induced Neuronal Extrusion - Healthy aging of the brain is highly dependent upon a range of protein quality control systems, and such quality control capacity is often disrupted in neurodegenerative disease. Recently it has come to light that diseased neurons can transfer toxic products, such as aggregated proteins, to neighboring cells, likely leading to the spread of pathology within the brain. How neurons generate and send out extracellular material in vivo is a question that must be addressed as we consider therapeutic intervention. Basic research can inform on mechanisms relevant to late onset neurodegenerative disease and can suggest avenues of treatment. Our studies take advantage of the enormous technical advantages in the simple animal model C. elegans permissive of experimentation that can yield mechanistic insight into neurodegeneration and neuroprotection biology. With high conservation of molecular function and a naturally transparent body plan, lessons learned from individual neuronal dynamics directly visualized and measured within the intact adult animal provides high predictive power for understanding key subcellular processes in more complex systems, including humans. We discovered that some stressed C. elegans neurons can extrude giant vesicles we call “exophers” that can be loaded with human disease protein aggregates. Exopher formation dramatically increases upon increased challenge to protein quality control in those neurons, including over-expressing human Alzheimer’s disease fragment Aβ1-42 or Huntington’s disease-associated polyQ protein. Aggregated proteins extruded in exophers are taken up by a glial pruning-like interaction with the neighboring cell, which attempts degradation. We hypothesize that exopher production is a previously unrecognized alternative route for adult neurons to clear protein aggregates and damaged organelles. Highly similar processes of giant vesicle budding and transfer of aggregates, lipids, and damaged organelles have been recently reported in C. elegans muscle, mouse cardiomyocytes, and mouse and human brain, strongly implying that discoveries we make about how this process operates in C. elegans will be widely relevant across species, including informing on elusive spreading mechanisms operating in human brain in neurodegenerative disease. We propose to exploit the considerable advantages of the C. elegans model (transparent body, facile genetic manipulation, exquisitely defined nervous system, powerful cell biology, short lifespan) to advance fundamental understanding of exopher biology. Our goals are to define the genetic and cell biological mechanisms operative in exopher formation with a focus on the cytoskeletal roles in exophergenesis: 1) define the genetic and cell biological mechanisms of microtubule dynamics that mediate exopher formation; 2) address how a neuron accomplishes scission that releases a large aggregate-filled domain, leaving behind an intact neuron. Our work should inform on a novel pathway of proteostasis control relevant to both healthy brain aging and neurodegenerative disease, defining a new area for study and for development of clinical interventions.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).