Necroptosis in the developing brain: role in neurodevelopmental disorders

Cell death is vital to various organismal developmental processes including brain development. Apoptosis, the most recognized programmed cell death, has been linked to several developmental processes and implicated in pruning cells to provide the ultimate tissue integrity. However, more recently, other forms of non-apoptotic programmed cell death have been identified, of which necroptosis is of predominant interest. Necroptosis is a regulated form of necrosis, activated under apoptotic-deficient conditions. Tumour necrosis factor (TNF) is a major activator of necroptosis, and the process is mediated by several kinases including receptor-interacting protein kinase (RIPK) and mixed lineage kinase domain-like protein (MLKL). Potential roles for necroptosis during brain development have been muted. Necroptosis has been implicated in mediating neurological disorders, and contributing to the severity of these disorders. Here we will review the literature on the role of necroptosis in neurodevelopment, summarizing its molecular mechanisms and highlighting potential implications for disorders of the developing brain.