MitochondriaAstrocyteEndoplasmic reticulum (ER)ATP depletionFall in mitochondrial membrane potentialIncreased ROSReduced expressionLow Ca2+ buffering capacityIncreased expressionMitochondrial dysfunctionDNA damageElevated glutamatelevelstBidAbnormal Rab5 dependent endycytosis?AggregatesImpairment of axonal transportAggregatesNeurofilament damageALS2DAXXO2-ProteasomeOHTNFalphaNONOApoptosisRAB5ARAC1H2O2MAPK Signaling PathwayMKK6NOS1Reactive Oxygen Species (ROS)CYTCp38Ca2+DNAMKK3PPP3CCPPP3CAPPP3CBNEFLNEFMp53 Signaling PathwayPRPHASK1NEFHPresynaptic neuronMicroglial cellMotor neuronNOL-ArginineONOO-EAAT2L-Glutamic acidL-Glutamic acidP53Neuron deathAPAF1CASP3CASP9ActivationL-Glutamic acidsynaptic transmission, glutamatergicIncrease incytosolic Ca2+Ca2+Derlin-1Accumulation ofmisfolded proteinsER stressDisturbance ofmitochondrial respirationCASP1BIDSOD1TOM40BCL2BCL2L1BAXBADUbiquitin proteosomedysfunctionCASP12TNFalphaTNFRGRIA1NONOSOD1ActivationCa2+ASK1ApoptosisReactive Oxygen Species (ROS)