MAP4K4 Activation Mediates Motor Neuron Degeneration in Amyotrophic Lateral Sclerosis

Summary: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting both upper and lower motor neurons (MNs). To date, its underlying mechanisms have yet to be clarified completely, and there are no truly effective treatments. Here, we show that MAP4K4, a MAP kinase family member, regulates MN death, with its suppression not only promoting survival but preventing neurite degeneration and decreasing mutant SOD1 levels through autophagy activation. Moreover, we report that MAP4K4 signaling specifically modulates MN viability via phosphorylated JNK3 and activation of the canonical c-Jun apoptotic pathway. Finally, we show the feasibility of MAP4K4 as a drug target by using an available MAP4K4-specific inhibitor, which improves survival of ESC and/or iPSC-derived MNs and MNs cultured from mouse spinal cords. In summary, our studies highlight a MAP4K4-initiated signaling cascade that induces MN degeneration, shedding light on the mechanism underlying MN degeneration and providing a druggable target for ALS therapeutics.: Wu et al. identify MAP4K4 as a key regulator of motor neuron degeneration in ALS. Reduction of MAP4K4 promotes motor neuron survival and neurite integrity under conditions of exogenous or endogenous stress both by directly attenuating c-Jun-mediated apoptosis and by activating autophagy, thereby reducing protein aggregation. Keywords: pluripotent stem cells, human motor neurons, amyotrophic, lateral sclerosis, MAP4K4, JNK, apoptosis, autophagy, FoxO1, therapeutics

Abstract licence: CC BY-NC

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