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29 Axonal Degeneration Disrupts Neural Connectivity and is a Key Early Contributor to the Pathogenesis of ALS Mechanisms of Axonal Degeneration Excess activation of glutamatergic, nicotinic, or voltage gated calcium channels drive influx of calcium from the extracellular space into cell Oxidative or ischemic stress drives calcium efflux through NCX channel from mitochondria Increased cytosolic calcium and cADPR Excess cytosolic calcium activates calpain-2 which cleaves cytoskeletal proteins activate the ER membrane ryanodine receptor, (NfL, others) and membrane-associated proteins (alpha-II spectrin) resulting in releasing the ER calcium store into the cytosol decreased axon stability and increased degradation (e.g., increased SBDP-145) AMPA=-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid