Mitochondria1Endoplasmic reticulum (ER)AstrocyteDNA damageIncreased expressionNeurofilament damageATP depletionFall in mitochondrial membrane potentialElevated glutamatelevelsImpairment of axonal transporttBidAggregatesMitochondrial dysfunctionMitochondriaAbnormal Rab5 dependent endycytosis?Increased ROSAggregatesReduced expressionLow Ca2+ buffering capacityGPX1Reactive Oxygen Species (ROS)PPP3CBNEFMALS2PRPHNEFLNOS1MAPK Signaling PathwayMKK6Ca2+ASK1RAC1PPP3CAp53 Signaling PathwayProteasomeDNAsynaptic transmission, glutamatergicMKK3PPP3CCApoptosisCuCATH2O2NODAXXH2Op38NORAB5AOHCCSNEFHTNFalphaCYTCO2-Presynaptic neuronMicroglial cellMotor neuronNOL-ArginineONOO-EAAT2L-Glutamic acidL-Glutamic acidTP53Neuron deathAPAF1CASP3CASP9ActivationL-Glutamic acidIncrease incytosolic Ca2+Ca2+Derlin-1Accumulation ofmisfolded proteinsER stressDisturbance ofmitochondrial respirationCASP1BIDSOD1TOM40BCL2BCL2L1BAXBADUbiquitin proteosomedysfunctionCASP12TNFalphaTNFRGRIA1NONOSOD1ActivationCa2+ASK1ApoptosisReactive Oxygen Species (ROS)SOD1SOD1