%0 Journal Article
%T Distinct mechanisms of axonal globule formation in mice expressing human wild type ¦Á-synuclein or dementia with Lewy bodies-linked P123H  -synuclein
%A Sekigawa Akio
%A Fujita Masayo
%A Sekiyama Kazunari
%A Takamatsu Yoshiki
%J Molecular Brain
%D 2012
%I BioMed Central
%R 10.1186/1756-6606-5-34
%X 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 ¦Â-synuclein (P123H ¦ÂS) were characterized by P123H ¦ÂS-immunoreactive axonal swellings (P123H ¦ÂS-globules). Therefore, the objectives of this study were to evaluate ¦Á-synuclein (¦ÁS)-immunoreactive axonal swellings (¦ÁS-globules) in the brains of tg mice expressing human wild-type ¦ÁS and to compare them with the globules in P123H ¦ÂS tg mice. Results In ¦ÁS tg mice, ¦ÁS-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 ¦ÂS-globules in P123H ¦ÂS tg mice. In the ¦ÁS-globules, frequent clustering and deformation of mitochondria were observed. These changes were associated with oxidative stress, based on staining of nitrated ¦ÁS and 4-hydroxy-2-nonenal (4-HNE). In accord with the absence of mitochondria in the P123H ¦ÂS-globules, staining of nitrated ¦ÁS and 4-HNE in these globules was weaker than that for ¦ÁS-globules. Leucine-rich repeat kinase 2 (LRRK2), the PARK8 of familial PD, was detected exclusively in ¦ÁS-globules, suggesting a specific role of this molecule in these globules. Conclusions Lysosomal pathology was similarly observed for both ¦ÁS- and P123H ¦ÂS-globules, while oxidative stress was associated with the ¦ÁS-globules, and to a lesser extent with the P123H ¦ÂS-globules. Other pathologies, such as mitochondrial alteration and LRRK2 accumulation, were exclusively detected for ¦ÁS-globules. Collectively, both ¦ÁS- and P123H ¦ÂS-globules were formed through similar but distinct pathogenic mechanisms. Our findings suggest that synuclein family members might contribute to diverse axonal pathologies.
%K ¦Á-synuclein
%K P123H ¦Â-synuclein
%K Parkinson¡¯s disease
%K Mitochondria
%K Lysosome
%K Transgenic mouse
%U http://www.molecularbrain.com/content/5/1/34