title: AMBRA1, a novel α-synuclein-binding protein, is implicated in the pathogenesis of multiple system atrophy.
abstract: The accumulation of abnormal α-synuclein is the major histopathological feature of Lewy body disease and multiple system atrophy (MSA), which are referred to as synucleinopathies. Cytoplasmic degradation systems, such as the autophagy-lysosome and proteasome pathways, are involved in their pathogenesis. Autophagy is tightly regulated by several upstream proteins including UNC-51-like kinase 1/2, beclin1, vacuolar protein sorting-associated protein 34 and autophagy/beclin1 regulator 1 (AMBRA1). Recently, we revealed that both cortical and brainstem-type Lewy bodies were immunopositive for several upstream proteins of autophagy. Therefore, we conducted the present study to elucidate the role of upstream proteins of autophagy in the pathogenesis of MSA. Pathological and biochemical analyses using human brain samples revealed that AMBRA1 is a component of the pathological hallmarks of MSA and upstream proteins of autophagy are impaired in the MSA brain. In vitro and in vivo analyses revealed a ninefold stronger affinity of AMBRA1 with α-synuclein phosphorylated at serine 129 compared with non-phosphorylated α-synuclein. Furthermore, a weak but significant correlation between AMBRA1 overexpression and reduction of abnormal α-synuclein was observed. Silencing AMBRA1 function caused aggregates of α-synuclein in the cytoplasm of mouse primary cultured neurons, which was simulated by the treatment of Bafilomycin, an autophagy inhibitor. Our results demonstrated for the first time that AMBRA1 is a novel hub binding protein of α-synuclein and plays a central role in the pathogenesis of MSA through the degradative dynamics of α-synuclein. These results raise the possibility that molecular modulation targeting AMBRA1 can be a promising candidate for the treatment of synucleinopathies.
authors.affiliation: Department of Neuropathology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Miki
authors.affiliation: Department of Neuropathology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Japan.
authors.forename: Kunikazu
authors.initials: K
authors.lastname: Tanji
authors.affiliation: Department of Neuropathology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Japan.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Mori
authors.affiliation: Department of Glycotechnology, Hirosaki University Graduate School of Medicine, Hirosaki, 036-8562, Japan.
authors.forename: Yota
authors.initials: Y
authors.lastname: Tatara
authors.affiliation: Department of Neurology, Hokkaido University Graduate School of Medicine, Sapporo, 060-8638, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Utsumi
authors.affiliation: Department of Neurology, Hokkaido University Graduate School of Medicine, Sapporo, 060-8638, Japan.
authors.forename: Hidenao
authors.initials: H
authors.lastname: Sasaki
authors.affiliation: Department of Pathological Neuroscience, Center for Bioresource-based Researches, Brain Research Institute, University of Niigata, Niigata, 951-8585, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Kakita
authors.affiliation: Department of Pathology, Brain Research Institute, University of Niigata, Niigata, 951-8585, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Department of Biological and Environmental Sciences and Technologies (DiSTeBA), Università del Salento, Lecce, Italy.|Department of Epidemiology and Preclinical Research, INMI L. Spallanzani IRCCS, Rome, Italy.
authors.forename: Gian Maria
authors.initials: GM
authors.lastname: Fimia
authors.affiliation: Department of Neuropathology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Wakabayashi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D019578:Multiple System Atrophy / Q000378:metabolism* / Q000473:pathology*; D059748:Proteolysis; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
chemical_list: C553334:AMBRA1 protein, human; D048868:Adaptor Proteins, Signal Transducing; C521754:Ambra1 protein, mouse; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; C497604:SNCA protein, human; D051844:alpha-Synuclein; D049452:Green Fluorescent Proteins
keywords: AMBRA1; autophagy; multiple system atrophy; synucleinopathy; α-synuclein