RRC ID 47304
著者 Miki Y, Tanji K, Mori F, Tatara Y, Utsumi J, Sasaki H, Kakita A, Takahashi H, Fimia GM, Wakabayashi K.
タイトル AMBRA1, a novel α-synuclein-binding protein, is implicated in the pathogenesis of multiple system atrophy.
ジャーナル Brain Pathol
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.
巻・号 28(1)
ページ 28-42
公開日 2018-1-1
DOI 10.1111/bpa.12461
PMID 27875637
PMC PMC8028368
MeSH Adaptor Proteins, Signal Transducing / genetics Adaptor Proteins, Signal Transducing / metabolism* Aged Aged, 80 and over Animals Autophagy / physiology* Brain / metabolism* Brain / pathology* Green Fluorescent Proteins / genetics Green Fluorescent Proteins / metabolism HEK293 Cells Humans Mice, Transgenic Microtubule-Associated Proteins / genetics Microtubule-Associated Proteins / metabolism Middle Aged Multiple System Atrophy / metabolism* Multiple System Atrophy / pathology* Proteolysis alpha-Synuclein / genetics alpha-Synuclein / metabolism
IF 5.568
引用数 7
リソース情報
実験動物マウス RBRC00806