MAP4K4 Activation Mediates Motor Neuron Degeneration in Amyotrophic Lateral Sclerosis

Abstract

Highlights d Blocking MAP4K4 attenuates the JNK3-cJun-induced apoptosis of motor neurons d MAP4K4 reduction stimulates autophagy to decrease mutant SOD1 in ALS motor neurons d A selective inhibitor of MAP4K4 activity potently improves motor neuron survival d MAP4K4 may constitute a therapeutic target for multiple types of ALS

JNK Signaling Pathway Involvement in Spinal Cord Neuron Development and Death

“…Wu and colleagues indicated that autophagy is dysfunctional in ALS MNs, and MAP4K4 siRNA-mediated silencing induces a restoration of autophagic physiological rate, potentially contributing to the reduction observed in mutant SOD1. This mechanism seems not to be mediated by mTOR signaling, whereas it seems to be FoxO1 protein-dependent, as phosphorylated FoxO1 levels increase after MAP4K4 inhibition, consistent with findings that JNK deficiency increases FoxO1-mediated autophagy [108,110].…”

“…Additionally, these experiments highlighted that JNK3 (rather than JNK1 and 2) is the active isoform mediator of cell death via MAP4K4 activation. Indeed, using both MAP4K4 and JNK3 siRNA simultaneously do not lead to any increased survival compared with blocking either alone, suggesting that the two molecules are part of the same pathway in MN degeneration [108]. In stressed MNs, the upregulation of MAP4K4 leads to an increase in phospho-JNK and phospho-c-Jun levels, with the subsequent increase of cleaved caspase3 levels and activation of the canonical apoptotic pathway.…”

“…Knocking down c-Jun also leads to MN number rescue. Neuritic degeneration is an early event in neuronal disorders and often precedes MN death: SOD1-mutant MNs in vitro show reduced neuritic length and number of nodes per MN, manifesting signs of degeneration; inhibition of MAP4K4-and presumably of JNK-has a positive effect on neurite outgrowth, by maintaining its structure and preventing neurons from degeneration [108].…”

JNK3 as Therapeutic Target and Biomarker in Neurodegenerative and Neurodevelopmental Brain Diseases

“…A recent study found that motor neuron (MN) death is caused by the activation of the MAP4K4-JNK3-c-Jun signaling pathway. In fact, inhibition of MAP4K4 has a neuroprotective effect on MNs and reduces mutant SOD1 accumulation by increasing cell autophagy, probably through FoxO1 [ 135 ].…”

Intensive care for human hearts in pluripotent stem cell models

“…While specific shortcomings in trial design or implementation are sometimes culpable, what these failed trials have in common uniformly is that none was based on proof of efficacy in human preclinical studies, before proceeding into the clinic. The use of hPSC-CMs toward drug discovery for cardioprotection was championed in our recent study creating novel inhibitors of the stress-activated kinase MAP4K4 (mitogen-activated protein kinase kinase kinase kinase-4) 65 , an upstream member of the MAPK superfamily with connections to Jun N-terminal kinase 66,67 and NFkB 68 , as well as to several non-canonical effectors as substrates 69,70 . The scientific case for MAP4K4 as a druggable target in heart muscle cell death began with human tissue characterization, finding that myocardial MAP4K4 was activated in end-stage heart failure regardless of cause (dilated, hypertrophic, ischemic, and anthracycline cardiomyopathy).…”