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The common ALS genes define three primary themes in pathophysiology: conformational instability and aggregation of proteins, impaired trafficking of RNA, and altered cytoskeletal dynamics. These converge on multiple secondary, downstream pathologic processes that include activation of endoplasmic reticulum (ER) stress and autophagy, proteasomal dysfunction, altered mitochondrial function, disturbed axonal transport, altered dendritic morphology, and excitotoxicity.
