Abstract:

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.

日本語要旨:

SOD1変異による遺伝性筋萎縮性側索硬化症(FALS)患者の剖検脳組織の生化学的解析により、変異型SOD1はシナプス領域に存在する多くの蛋白と強い結合した蛋白複合体を形成していることを示し、このような変化がFALSにおける神経機能低下機序の一部となっている可能性を示した。