Necroptosis: who knew there were so many interesting ways to die?

Conventional knowledge considered apoptosis as the sole form of programmed cell death during development, homeostasis and diseases, whereas necrosis was regarded as an unregulated and uncontrollable process. Recent revelations suggest that necrosis can also occur in a regulated, caspase-independent manner and shares characteristics with both necrosis and apoptosis. The major cell death processes namely apoptosis, autophagy and necrosis are interlinked and contain many common regulatory mechanisms. Mounting evidence indicates that necroptosis contributes to the pathogenesis of various diseases, including ischemic stroke, traumatic brain injury, neurodegenerative disorders and brain tumor. We present here an overview of the molecular mechanisms governing necroptosis and its connection with apoptosis and autophagy processes. Further, the necroptosis mechanisms underlying the neurodegeneration during ischemia reperfusion (I/R) injury are described, with an emphasis on the key proteins involved in this type of cell death. Knowledge regarding programmed cell death (PCD) with relevance to necroptosis may play a significant role in debilitating brain disorders.