AXONAL-TRANSPORT OF MUTANT SUPEROXIDE-DISMUTASE-1 AND FOCAL AXONAL ABNORMALITIES IN THE PROXIMAL AXONS OF TRANSGENIC MICE

Superoxide dismutase 1 (SOD1), a ubiquitously expressed enzyme, detoxi fies superoxide radicals and participates in copper homeostasis. Mutat ions in this enzyme have been linked to a subset of autosomal dominant cases of familial amyotrophic lateral sclerosis (FALS), a disorder ch aracterized by selective degeneration of motor neurons. Transgenic mic e expressing FALS mutant human (Hu) SOD1 at high levels develop a moto r neuron disease, indicating that mutant Hu SOD1 gains properties that are particularly toxic to motor neurons. In this report, we demonstra te that transgenic mice expressing Hu SOD1 with the G37R FALS mutation , but not mice expressing wild-type enzyme, develop focal increases in immunoreactivity in the proximal axons of spinal motor neurons. This SOD1 immunoreactivity and immunoreactivity to hypophosphorylated neuro filament H epitopes are found adjacent to small vacuoles in axons. Usi ng metabolic radiolabeling methods, we show that mutant G37R HuSOD1 as well as endogenous mouse SOD1 are transported anterograde in slow com ponent b in motor and sensory axons of the sciatic nerve. Together, th ese findings suggest that anterogradely transported mutant SOD1 may ac t locally to damage motor axons. (C) 1998 Academic Press.