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Open Access Research

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

Akio Sekigawa1, Masayo Fujita1, Kazunari Sekiyama1, Yoshiki Takamatsu1, Taku Hatano2, Edward Rockenstein3, Albert R La Spada45, Eliezer Masliah3 and Makoto Hashimoto1*

Author Affiliations

1 Division of Sensory and Motor Systems, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan

2 Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Tokyo, Bunkyo, 113-8421, Japan

3 Department of Neurosciences, University of California-San Diego, La Jolla, CA, 92093-0624, USA

4 Department of Pediatrics, and Cellular and Molecular Medicine, University of California-San Diego, La Jolla, CA, 92093-0624, USA

5 Rady Children’s Hospital, San Diego, CA, 92193, USA

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Molecular Brain 2012, 5:34  doi:10.1186/1756-6606-5-34

Published: 26 September 2012

Abstract

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 β-synuclein (P123H βS) were characterized by P123H βS-immunoreactive axonal swellings (P123H βS-globules). Therefore, the objectives of this study were to evaluate α-synuclein (αS)-immunoreactive axonal swellings (αS-globules) in the brains of tg mice expressing human wild-type αS and to compare them with the globules in P123H βS tg mice.

Results

In αS tg mice, αS-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 βS-globules in P123H βS tg mice. In the αS-globules, frequent clustering and deformation of mitochondria were observed. These changes were associated with oxidative stress, based on staining of nitrated αS and 4-hydroxy-2-nonenal (4-HNE). In accord with the absence of mitochondria in the P123H βS-globules, staining of nitrated αS and 4-HNE in these globules was weaker than that for αS-globules. Leucine-rich repeat kinase 2 (LRRK2), the PARK8 of familial PD, was detected exclusively in αS-globules, suggesting a specific role of this molecule in these globules.

Conclusions

Lysosomal pathology was similarly observed for both αS- and P123H βS-globules, while oxidative stress was associated with the αS-globules, and to a lesser extent with the P123H βS-globules. Other pathologies, such as mitochondrial alteration and LRRK2 accumulation, were exclusively detected for αS-globules. Collectively, both αS- and P123H βS-globules were formed through similar but distinct pathogenic mechanisms. Our findings suggest that synuclein family members might contribute to diverse axonal pathologies.

Keywords:
α-synuclein; P123H β-synuclein; Parkinson’s disease; Mitochondria; Lysosome; Transgenic mouse