MitochondriaEndoplasmic reticulum (ER)AstrocyteIncreased ROSAggregatesIncreased expressiontBidDNA damageAbnormal Rab5 dependent endycytosis?Reduced expressionElevated glutamatelevelsLow Ca2+ buffering capacityAggregatesMitochondrial dysfunctionNeurofilament damageATP depletionFall in mitochondrial membrane potentialImpairment of axonal transportRAB5ANOS1RAC1p53 Signaling PathwayApoptosisMAPK Signaling PathwayCYTCDNATNFalphaPPP3CBProteasomeCa2+NEFHp38NEFHASK1NONEFMPPP3CAMKK6MKK3NEFLDAXXReactive Oxygen Species (ROS)NOPPP3CCALS2Presynaptic 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+ASK1Apoptosis