Necrotic cell death and neurodegeneration: The involvement of endocytosis and intracellular trafficking.

Necrosis, one of the two main types of cell death, contributes critically in many devastating pathological conditions in human, including stroke, ischemia, trauma and neurodegenerative diseases. However, unlike apoptosis, the molecular mechanisms underlying necrotic cell death and neurodegeneration are poorly understood. Caenorhabditis elegans offers a powerful platform for a thorough and systematic dissection of the molecular basis of necrotic cell death. Similarly to humans, neuronal necrosis can be induced by several well-characterized genetic lesions and by adverse environmental conditions in the nematode. The availability of precisely-defined C. elegans neurodegeneration models provides a unique opportunity for comprehensive delineation of the cellular and molecular mechanisms mediating necrotic cell death. Through genetic dissection of such models, we recently uncovered an unexpected requirement for specific proteins involved in endocytosis and intracellular trafficking, in the execution of necrosis. Moreover, initiation of necrotic cell death is accompanied by a sharp increase in the formation of early and recycling endosomes, which subsequently disintegrate during the final stage of cell death. These findings implicate endocytic and intracellular trafficking processes in the cellular destruction during necrosis. Indeed, endocytosis synergizes with two other essential cellular processes, autophagy and lysosomal proteolysis to facilitate necrotic neurodegeneration. In this commentary, we consider the contribution of endocytosis and intracellular trafficking to cell injury and discuss the crosstalk between these processes and other molecular mechanisms that mediate necrosis.