View article

The mechanisms of human mutant superoxide dismutase‐1 (mSOD1) toxicity to motor neurons (MNs) are unresolved. We show that MNs in G93A‐mSOD1 transgenic mice undergo slow degeneration lacking similarity to apoptosis structurally and biochemically. It is characterized by somal and mitochondrial swelling and formation of DNA single‐strand breaks prior to double‐strand breaks occurring in nuclear and mitochondrial DNA. p53 and p73 are activated in degenerating MNs, but without nuclear import. The MN death is independent of activation of caspases‐1, ‐3, and ‐8 or apoptosis‐inducing factor within MNs, with a blockade of apoptosis possibly mediated by Aven up‐regulation. MN swelling is associated with compromised Na,K‐ATPase activity and aggregation. mSOD1 mouse MNs accumulate mitochondria from the axon terminals and generate higher levels of superoxide, nitric oxide, and peroxynitrite …