The excessive release of the neurotransmitter glutamate causes high levels of Ca2+ to enter neuronal cells. This leads to neuronal excitotoxicity and the degeneration of axons and dendrites. Excitotoxicity is involved in several human neuronal pathologies, including Alzheimer's disease (AD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Although the steps leading to axonal degeneration, such as opening of the mitochondrial permeability transition pore (mPTP), are known, the signalling pathways that trigger degeneration are not fully understood. In their Research Article (Hernaández et al., 2018), Felipe Court and colleagues describe that axonal degeneration following glutamate excitotoxicity is controlled by necroptosis. They show that the inhibition of receptor interacting kinase 1 (RIPK1), RIPK3 or the mediator of necroptosis MLKL blocks events in axonal degeneration, such as Ca2+ dysregulation in the axonal compartment, mPTP opening and mitochondrial depolarisation. Importantly, excitotoxicity leads to canonical apoptosis in the cell soma while necroptotic axonal degeneration occurs, highlighting that independent cell death mechanisms are activated under the same stimuli. Identification of a necroptotic pathway in axonal degeneration might allow for therapeutic strategies tackling neuro-pathological disorders.
Necroptosis is key to axonal degeneration after excitotoxicity
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Necroptosis is key to axonal degeneration after excitotoxicity. J Cell Sci 15 November 2018; 131 (22): e2202. doi:
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