Sortilin acts as an endocytic receptor for α‐synuclein fibril
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- Shun Ishiyama
- Division of Neurology, Department of Neuroscience & Sensory Organs Tohoku University Graduate School of Medicine Sendai Japan
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- Takafumi Hasegawa
- Division of Neurology, Department of Neuroscience & Sensory Organs Tohoku University Graduate School of Medicine Sendai Japan
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- Naoto Sugeno
- Division of Neurology, Department of Neuroscience & Sensory Organs Tohoku University Graduate School of Medicine Sendai Japan
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- Junpei Kobayashi
- Division of Neurology, Department of Neuroscience & Sensory Organs Tohoku University Graduate School of Medicine Sendai Japan
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- Shun Yoshida
- Division of Neurology, Department of Neuroscience & Sensory Organs Tohoku University Graduate School of Medicine Sendai Japan
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- Yasuo Miki
- Department of Neuropathology Institute of Brain Science, Hirosaki University Graduate School of Medicine Hirosaki Japan
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- Koichi Wakabayashi
- Department of Neuropathology Institute of Brain Science, Hirosaki University Graduate School of Medicine Hirosaki Japan
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- Mitsunori Fukuda
- Laboratory of Membrane Trafficking Mechanisms, Department of Integrative Life Sciences, Graduate School of Life Sciences Tohoku University Sendai Japan
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- Yasushi Kawata
- Department of Chemistry and Biotechnology, Graduate School of Engineering Tottori University Tottori Japan
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- Takaaki Nakamura
- Division of Neurology, Department of Neuroscience & Sensory Organs Tohoku University Graduate School of Medicine Sendai Japan
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- Kazuki Sato
- Division of Neurology, Department of Neuroscience & Sensory Organs Tohoku University Graduate School of Medicine Sendai Japan
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- Michinori Ezura
- Division of Neurology, Department of Neuroscience & Sensory Organs Tohoku University Graduate School of Medicine Sendai Japan
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- Akio Kikuchi
- Division of Neurology, Department of Neuroscience & Sensory Organs Tohoku University Graduate School of Medicine Sendai Japan
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- Atsushi Takeda
- Department of Neurology National Hospital Organization Sendai‐Nishitaga Hospital Sendai Japan
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- Masashi Aoki
- Division of Neurology, Department of Neuroscience & Sensory Organs Tohoku University Graduate School of Medicine Sendai Japan
書誌事項
- 公開日
- 2023-06-05
- 資源種別
- journal article
- 権利情報
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- http://creativecommons.org/licenses/by/4.0/
- DOI
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- 10.1096/fj.202201605rr
- 公開者
- Wiley
この論文をさがす
説明
<jats:title>Abstract</jats:title> <jats:p>Cell‐to‐cell spreading of misfolded α‐synuclein (αSYN) is supposed to play a key role in the pathological progression of Parkinson's disease (PD) and other synucleinopathies. Receptor‐mediated endocytosis has been shown to contributes to the uptake of αSYN in both neuronal and glial cells. To determine the receptor involved in αSYN endocytosis on the cell surface, we performed unbiased, and comprehensive screening using a membrane protein library of the mouse whole brain combined with affinity chromatography and mass spectrometry. The candidate molecules hit in the initial screening were validated by co‐immunoprecipitation using cultured cells; sortilin, a vacuolar protein sorting 10 protein family sorting receptor, exhibited the strongest binding to αSYN fibrils. Notably, the intracellular uptake of fibrillar αSYN was slightly but significantly altered, depending on the expression level of sortilin on the cell surface, and time‐lapse image analyses revealed the concomitant internalization and endosomal sorting of αSYN fibrils and sortilin. Domain deletion in the extracellular portion of sortilin revealed that the ten conserved cysteines (10CC) segment of sortilin was involved in the binding and endocytosis of fibrillar αSYN; importantly, pretreatment with a 10CC domain‐specific antibody significantly hindered αSYN fibril uptake. The presence of sortilin in the core structure of Lewy bodies and glial cytoplasmic inclusions in the brain of synucleinopathy patients was confirmed via immunohistochemistry, and the expression level of sortilin in mesencephalic dopaminergic neurons may be altered with disease progression. These results provide compelling evidence that sortilin acts as an endocytic receptor for pathogenic form of αSYN, and yields important insight for the development of disease‐modifying targets for synucleinopathies.</jats:p>
収録刊行物
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- The FASEB Journal
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The FASEB Journal 37 (7), e23017-, 2023-06-05
Wiley
