title: Accumulated α-synuclein affects the progression of GM2 gangliosidoses.
abstract: The accumulation of α-synuclein (ASyn) has been observed in several lysosomal storage diseases (LSDs) but it remains unclear if ASyn accumulation contributes to LSD pathology. ASyn also accumulates in the neurons of Sandhoff disease (SD) patients and SD model mice (Hexb-/- ASyn+/+ mice). SD is a lysosomal storage disorder caused by the absence of a functional β-subunit on the β-hexosaminidase A and B enzymes, which leads to the accumulation of ganglioside in the central nervous system. Here, we explored the role of accumulated ASyn in the progression of Hexb-/- mice by creating a Hexb-/- ASyn-/- double-knockout mice. Our results show that Hexb-/- ASyn-/- mice demonstrated active microglia levels and less dopaminergic neuron loss, without altering the neuronal storage of ganglioside. The autophagy and ubiquitin proteasome pathways are defective in the neurons of Hexb-/- ASyn+/+ mice. In ultrastructural physiological studies, the mitochondria structures look degenerated and dysfunctional. As a result, expression of manganese superoxide dismutase 2 are reduced, and reactive oxygen species-mediated oxidative damage in the neurons of Hexb-/- ASyn+/+ mice. Interestingly, these dysfunctions improved in Hexb-/- ASyn-/- mice. But any clinical improvement were hardly observed in Hexb-/- ASyn-/- mice. Taken together, these findings suggest that ASyn accumulation plays an important role in the pathogenesis of neuropathy in SD and other LSDs, and is therefore a target for novel therapies.
authors.affiliation: Department of Psychiatry, Yokohama City University School of Medicine, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Department of Pathology, Yokohama City University School of Medicine, Japan. Electronic address: yamaguchiakira@mac.com.
authors.forename: Akira
authors.initials: A
authors.lastname: Yamaguchi
authors.affiliation: Department of Pathology, Yokohama City University School of Medicine, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Yamanaka
authors.affiliation: Department of Pathology, Yokohama City University School of Medicine, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Kanzaki
authors.affiliation: Department of Pathology, Yokohama City University School of Medicine, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Kawashima
authors.affiliation: Department of Psychiatry, Yokohama City University School of Medicine, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Togo
authors.affiliation: Department of Psychiatry, Yokohama City University School of Medicine, Japan.
authors.forename: Omi
authors.initials: O
authors.lastname: Katsuse
authors.affiliation: Department of Dermatology, Yokohama City University School of Medicine, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Koumitsu
authors.affiliation: Department of Psychiatry, Yokohama City University School of Medicine, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Aoki
authors.affiliation: Department of Psychiatry, Juntendo University School of Medicine, Japan.
authors.forename: Eizo
authors.initials: E
authors.lastname: Iseki
authors.affiliation: Department of Psychiatry, Yokohama City University School of Medicine, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kosaka
authors.affiliation: Department of Pathology, Yokohama City University School of Medicine, Japan.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Yamaguchi
authors.affiliation: Tokyo Metropolitan Institute of Medical Science, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Hashimoto
authors.affiliation: Department of Pathology, Yokohama City University School of Medicine, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Aoki
authors.affiliation: Department of Psychiatry, Yokohama City University School of Medicine, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hirayasu
keywords: Alpha-synuclein; Autophagy; GM2 gangliosidoses; Manganese superoxide dismutase 2; Reactive oxygen species; Sandhoff disease