Programmed Cell Death and Cellular Stress: Insights from Caenorhabditis elegans pink-1 and icd-1

Programmed cell death is a critical process that is necessary to cull damaged cells as well as eliminate unnecessary cells during normal development. Improper regulation of this process can result in neurodegenerative diseases and cancer. While developmental cell death involves the death of healthy cells, most programmed cell death eliminates unhealthy cells that are unable to recover from stress. There are various different types of cellular stress that can result in cell death including oxidative and endoplasmic reticulum stress. The transparent nematode worm Caenorhabditis elegans is an ideal model in which to study programmed cell death due to its short life cycle and genetic tractability. The genes controlling cell death were originally discovered in this organism and the pathway is conserved from C. elegans to humans.;Parkinson's disease is a neurodegenerative disorder that results in progressive loss of motor function. Though the majority of cases are sporadic, a small proportion are due to genetic mutations. One of the proteins involved in familial Parkinson's disease, PINK1, is a mitochondrial serine-threonine kinase that protects mitochondria from oxidative stress and aids in the initiation of mitophagy. Loss of PINK1 function results in increased cell death in humans and Drosophila. In C. elegans PINK-1 instead functions as an activator of programmed cell death. This pro-apoptotic function is due to the N-terminal domain rather than kinase function.;The accumulation of misfolded proteins in the endoplasmic reticulum results in programmed cell death if the unfolded protein response fails to resolve the stress. In C. elegans loss of ICD-1, the homolog of βNAC, results in excessive ectopic cell death. Loss of ICD-1 function results in the inappropriate targeting of nascent peptides to the endoplasmic reticulum resulting in misfolded protein stress. The cell death induced is completely dependent on CED-4, the Apaf1 homolog, but is more dependent on both the canonical caspase CED-3 in the early-stage embryos and the non-canonical caspase CSP-1 in late-stage embryos. Under stress calcium can be released by the endoplasmic reticulum into the cytoplasm. The calpain CLP-2, a calcium activated protease, is also necessary for late-stage embryonic cell deaths in ICD-1 depleted animals.