title: Distinct mechanisms of axonal globule formation in mice expressing human wild type α-synuclein or dementia with Lewy bodies-linked P123H β-synuclein.
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.
authors.affiliation: Division of Sensory and Motor Systems, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Sekigawa
authors.forename: Masayo
authors.initials: M
authors.lastname: Fujita
authors.forename: Kazunari
authors.initials: K
authors.lastname: Sekiyama
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Takamatsu
authors.forename: Taku
authors.initials: T
authors.lastname: Hatano
authors.forename: Edward
authors.initials: E
authors.lastname: Rockenstein
authors.forename: Albert R
authors.initials: AR
authors.lastname: La Spada
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Makoto
authors.initials: M
authors.lastname: Hashimoto
mesh_terms: D000375:Aging; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D003704:Dementia / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D020961:Lewy Body Disease / Q000378:metabolism / Q000473:pathology*; D008247:Lysosomes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D050505:Mutant Proteins / Q000378:metabolism*; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D012307:Risk Factors; D051844:alpha-Synuclein / Q000378:metabolism*; D051846:beta-Synuclein / Q000378:metabolism*
chemical_list: D050505:Mutant Proteins; C497604:SNCA protein, human; C497607:SNCB protein, human; D051844:alpha-Synuclein; D051846:beta-Synuclein