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.

AMBRA1, a novel α-synuclein-binding protein, is implicated in the pathogenesis of multiple system atrophy / Miki, Yasuo; Tanji, Kunikazu; Mori, Fumiaki; Tatara, Yota; Utsumi, Jun; Sasaki, Hidenao; Kakita, Akiyoshi; Takahashi, Hitoshi; Fimia, Gian Maria; Wakabayashi, Koichi. - In: BRAIN PATHOLOGY. - ISSN 1015-6305. - Epub ahead of print:(2016), pp. 1-15. [10.1111/bpa.12461]

AMBRA1, a novel α-synuclein-binding protein, is implicated in the pathogenesis of multiple system atrophy

Fimia Gian Maria;
2016

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.
2016
AMBRA1; autophagy; multiple system atrophy; synucleinopathy; α-synuclein
01 Pubblicazione su rivista::01a Articolo in rivista
AMBRA1, a novel α-synuclein-binding protein, is implicated in the pathogenesis of multiple system atrophy / Miki, Yasuo; Tanji, Kunikazu; Mori, Fumiaki; Tatara, Yota; Utsumi, Jun; Sasaki, Hidenao; Kakita, Akiyoshi; Takahashi, Hitoshi; Fimia, Gian Maria; Wakabayashi, Koichi. - In: BRAIN PATHOLOGY. - ISSN 1015-6305. - Epub ahead of print:(2016), pp. 1-15. [10.1111/bpa.12461]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1319295
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