Distinct mechanisms of axonal globule formation in mice expressing human wild type α-synuclein or dementia with Lewy bodies-linked P123H β-synuclein

Background: Axonopathy is critical in the early pathogenesis of neurodegenerative diseases, including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Axonal swellings such as globules and spheroids are a distinct feature of axonopathy and our recent study showed that transgenic (tg) mice expressing DLB-linked P123H beta-synuclein (P123H beta S) were characterized by P123H beta S-immunoreactive axonal swellings (P123H beta S-globules). Therefore, the objectives of this study were to evaluate alpha-synuclein (alpha S)-immunoreactive axonal swellings (alpha S-globules) in the brains of tg mice expressing human wild-type alpha S and to compare them with the globules in P123H beta S tg mice. Results: In alpha S tg mice, alpha S-globules were formed in an age-dependent manner in various brain regions, including the thalamus and basal ganglia. These globules were composed of autophagosome-like membranous structures and were reminiscent of P123H beta S-globules in P123H beta S tg mice. In the alpha S-globules, frequent clustering and deformation of mitochondria were observed. These changes were associated with oxidative stress, based on staining of nitrated alpha S and 4-hydroxy-2-nonenal (4-HNE). In accord with the absence of mitochondria in the P123H beta S-globules, staining of nitrated alpha S and 4-HNE in these globules was weaker than that for alpha S-globules. Leucine-rich repeat kinase 2 (LRRK2), the PARK8 of familial PD, was detected exclusively in alpha S-globules, suggesting a specific role of this molecule in these globules. Conclusions: Lysosomal pathology was similarly observed for both alpha S- and P123H beta S-globules, while oxidative stress was associated with the alpha S-globules, and to a lesser extent with the P123H beta S-globules. Other pathologies, such as mitochondrial alteration and LRRK2 accumulation, were exclusively detected for alpha S-globules. Collectively, both alpha S- and P123H beta S-globules were formed through similar but distinct pathogenic mechanisms. Our findings suggest that synuclein family members might contribute to diverse axonal pathologies.