Project Details
Projekt
Interorgan communication regulating stress exopher production in muscle cells
Subject Area
Biochemistry
Cell Biology
Cell Biology
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 531902955
The maintenance of protein homeostasis (proteostasis) in cells is of fundamental importance for the survival of all organisms. Failure to repair or eliminate damaged and misfolded proteins can lead to the formation of toxic protein aggregates that compromise the function and viability of cells. Such proteotoxic stress conditions are considered to be the main cause of several devastating human diseases known as proteinopathies, such as Alzheimer's or Parkinson's disease. In these diseases, self-templating amyloid aggregates appear to propagate from one cell to another causing a spread of proteotoxic stress condition throughout the tissue. A possible major transport pathway that cause the spread of protein aggregates has been identified recently. Individual long-lived cells such as neurons and muscle cells sequestrate and secrete their cellular waste including amyloid aggregates in giant vesicles called exophers. These vesicles are then digested by nearby phagocytic cells. While this pathway allows individual cells to cope with excessive stress that overwhelms their intracellular proteostasis capacity, it could have a detrimental effect on organismal proteostasis if the proteotoxic waste vesicles are not rapidly cleared by phagocytes. Thus, to prevent a spread of proteotoxic particles, an intercellular communication is required that synchronizes the production of exophers with their elimination in distant cells. We recently discovered such an interorgan communication pathway in the model organism Caenorhabditis elegans. In this organism, the activity of the exopher pathway in individual cells seems to be regulated not only by an intrinsic activating stress signal but also by an extrinsic inactivating signal when the proteostasis capacity in surrounding tissue cells is insufficient. The molecular basis of this intercellular communication is currently unclear. A deeper insight into the mechanisms controlling exopher production and elimination could have a great impact on understanding the propagation of proteotoxic stress conditions in human proteinopathies. The identification of extracellular signaling molecules that modulate the activity of the exopher pathway could even lead to new therapeutic approaches for protein aggregation diseases. We will therefore systematically investigate the interorgan communication pathways that control exopher production in individual cells and their elimination in distant scavenger cells in vivo using C. elegans as a model system.
DFG Programme
Research Units
