Sortilin acts as an endocytic receptor for α‐synuclein fibril

Author:

Ishiyama Shun1,Hasegawa Takafumi1ORCID,Sugeno Naoto1,Kobayashi Junpei1,Yoshida Shun12,Miki Yasuo3,Wakabayashi Koichi3,Fukuda Mitsunori4ORCID,Kawata Yasushi56,Nakamura Takaaki1,Sato Kazuki1,Ezura Michinori17,Kikuchi Akio18,Takeda Atsushi9,Aoki Masashi1

Affiliation:

1. Division of Neurology, Department of Neuroscience & Sensory Organs Tohoku University Graduate School of Medicine Sendai Japan

2. Department of Neurology National Hospital Organization Yonezawa Hospital Yonezawa Japan

3. Department of Neuropathology Institute of Brain Science, Hirosaki University Graduate School of Medicine Hirosaki Japan

4. Laboratory of Membrane Trafficking Mechanisms, Department of Integrative Life Sciences, Graduate School of Life Sciences Tohoku University Sendai Japan

5. Department of Chemistry and Biotechnology, Graduate School of Engineering Tottori University Tottori Japan

6. Department of Biomedical Sciences Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University Tottori Japan

7. Department of Neurology Southern Tohoku General Hospital Koriyama Japan

8. Department of Occupational Therapy Yamagata Prefectural University of Health Sciences Yamagata Japan

9. Department of Neurology National Hospital Organization Sendai‐Nishitaga Hospital Sendai Japan

Abstract

AbstractCell‐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.

Funder

Japan Agency for Medical Research and Development

Ministry of Education, Culture, Sports, Science and Technology

Publisher

Wiley

Subject

Genetics,Molecular Biology,Biochemistry,Biotechnology

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