Accumulation of β- and γ-synucleins in the ubiquitin carboxyl-terminal hydrolase L1-deficient gad mouse

Abstract

The synuclein family includes three isoforms, termed α, β and γ. α-Synuclein accumulates in various pathological lesions resulting from neurodegenerative disorders including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy. However, neither β- nor γ-synuclein has been detected in Lewy bodies, and thus it is unclear whether these isoforms contribute to neurological pathology. In the present study, we used immunohistochemistry to demonstrate accelerated accumulation of β- and γ-synucleins in axonal spheroids in gracile axonal dystrophy (gad) mice, which do not express ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1). γ-Synuclein immunoreactivity in the spheroids appeared in the gracile nucleus at 3 weeks of age and was maintained until 32 weeks. β-Synuclein immunoreactivity appeared in spheroids around 12 weeks of age. In contrast, α-synuclein immunoreactivity was barely detectable in spheroids. Immunoreactivity for synaptophysin and ubiquitin were either faint or undetectable in spheroids. Given that UCH-L1 deficiency results in axonal degeneration and spheroid formation, our findings suggest that β- and γ-synuclein participate in the pathogenesis of axonal swelling in gad mice.