Misfolded SOD1 forms high-density molecular complexes with synaptic molecules in mutant SOD1-linked familial amyotrophic lateral sclerosis cases.

Mutations in the superoxide dismutase 1 (sod1) gene cause familial amyotrophic lateral sclerosis (FALS), likely due to the toxic properties of misfolded mutant SOD1 protein. Here we report identification of various synaptic molecules forming molecular complexes with misfolded SOD1 in mutant SOD1-associated FALS patient tissues as well as in cellular FALS models. In the FALS cellular model system, we found that membrane depolarization that mimics synaptic hyperactivation/excitotoxicity could cause misfolding of mutant SOD, as well as acceleration of misfolded SOD1–synaptic protein complex formation. These results suggest that inhibition of synaptic release mechanism by association of misfolded SOD1 with synaptic molecules plays a role in the dysfunction of FALS.