Differential screening of mutated SOD1 transgenic mice reveals early up-regulation of a fast axonal transport component in spinal cord motor neurons

In the present study we analyze the molecular mechanisms underlying motor n euron degeneration in familial amyotrophic lateral sclerosis (FALS). For th is, we used a transgenic mouse model expressing the Cu/Zn superoxide dismut ase (SOD1) gene with a Gly(86) to Arg (G86R) mutation equivalent to that fo und in a subset of human FALS. Using an optimized suppression subtractive h ybridization method, a cDNA specifically up-regulated during the asymptomat ic phase in the lumbar spinal cord of G86R mice was identified by sequence analysis as the KIF3-associated protein (KAP3), a regulator of fast axonal transport. RT-PCR analysis revealed that KAP3 induction was an early event arising long before axonal degeneration. Immunohistochemical studies furthe r revealed that KAP3 protein predominantly accumulates in large motor neuro ns of the ventral spinal cord. We further demonstrated that KAP3 up-regulat ion occurs independent of any change in the other components of the kinesin II complex. However, since the ubiquitous KIF1A motor is up-regulated, our results show an early and complex rearrangement of the fast axonal transpo rt machinery in the course of FALS pathology. (C) 2000 Academic Press.