Mitochondria1AstrocyteEndoplasmic reticulum (ER)Increased expressionNeurofilament damageAggregatesImpairment of axonal transportIncreased ROSATP depletionFall in mitochondrial membrane potentialReduced expressionDNALow Ca2+ buffering capacityDNA damageMitochondriaAggregatesAbnormal Rab5 dependent endycytosis?tBidMitochondrial dysfunctionElevated glutamatelevelsNOS1ASK1MAPK Signaling PathwayNEFHCCSMKK6NEFMPPP3CBCuCYTCALS2p38PPP3CACa2+ApoptosisNONEFLCATRAC1GPX1Reactive Oxygen Species (ROS)TNFalphaMKK3H2ODAXXPPP3CCRAB5AOHsynaptic transmission, glutamatergicPRPHNOO2-ProteasomeH2O2p53 Signaling PathwayPresynaptic 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