| First Author | Sekigawa A | Year | 2012 |
| Journal | Mol Brain | Volume | 5 |
| Pages | 34 | PubMed ID | 23013868 |
| Mgi Jnum | J:324569 | Mgi Id | MGI:7280804 |
| Doi | 10.1186/1756-6606-5-34 | Citation | Sekigawa A, et al. (2012) Distinct mechanisms of axonal globule formation in mice expressing human wild type alpha-synuclein or dementia with Lewy bodies-linked P123H beta-synuclein. Mol Brain 5:34 |
| abstractText | 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 betaS) were characterized by P123H betaS-immunoreactive axonal swellings (P123H betaS-globules). Therefore, the objectives of this study were to evaluate alpha-synuclein (alphaS)-immunoreactive axonal swellings (alphaS-globules) in the brains of tg mice expressing human wild-type alphaS and to compare them with the globules in P123H betaS tg mice. RESULTS: In alphaS tg mice, alphaS-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 betaS-globules in P123H betaS tg mice. In the alphaS-globules, frequent clustering and deformation of mitochondria were observed. These changes were associated with oxidative stress, based on staining of nitrated alphaS and 4-hydroxy-2-nonenal (4-HNE). In accord with the absence of mitochondria in the P123H betaS-globules, staining of nitrated alphaS and 4-HNE in these globules was weaker than that for alphaS-globules. Leucine-rich repeat kinase 2 (LRRK2), the PARK8 of familial PD, was detected exclusively in alphaS-globules, suggesting a specific role of this molecule in these globules. CONCLUSIONS: Lysosomal pathology was similarly observed for both alphaS- and P123H betaS-globules, while oxidative stress was associated with the alphaS-globules, and to a lesser extent with the P123H betaS-globules. Other pathologies, such as mitochondrial alteration and LRRK2 accumulation, were exclusively detected for alphaS-globules. Collectively, both alphaS- and P123H betaS-globules were formed through similar but distinct pathogenic mechanisms. Our findings suggest that synuclein family members might contribute to diverse axonal pathologies. |
