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LRRK2 regulates AP2M1 phosphorylation cycles to mediate endocytosis and dopaminergic neurodegeneration

Qinfang Liu, Judith Bautista-Gomez, Daniel A. Higgins, Jianzhong Yu, View ORCID ProfileYulan Xiong
doi: https://doi.org/10.1101/2020.05.27.119388
Qinfang Liu
1Department of Anatomy & Physiology, Kansas State University College of Veterinary Medicine, Manhattan, KS 66506, USA
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Judith Bautista-Gomez
2Department of Chemistry, Kansas State University, Manhattan, KS 66506, USA
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Daniel A. Higgins
2Department of Chemistry, Kansas State University, Manhattan, KS 66506, USA
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Jianzhong Yu
1Department of Anatomy & Physiology, Kansas State University College of Veterinary Medicine, Manhattan, KS 66506, USA
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  • For correspondence: yulanxiong@ksu.edu jianzhongyu@ksu.edu
Yulan Xiong
1Department of Anatomy & Physiology, Kansas State University College of Veterinary Medicine, Manhattan, KS 66506, USA
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  • ORCID record for Yulan Xiong
  • For correspondence: yulanxiong@ksu.edu jianzhongyu@ksu.edu
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Abstract

Recent genetic evidence revealed endocytic pathway plays a major role in Parkinson’s disease (PD). However, the molecular mechanism is poorly understood. Here we report that LRRK2, the most genetic cause of PD, binds to and phosphorylates AP2M1, the core component of endocytosis recently implicated in PD risk. Both knockout and overexpression of LRRK2 cause abnormal AP2M1 phosphorylation cycle and in turn endocytic defects. Mechanistically, knockout of LRRK2 decreases AP2M1 phosphorylation required for the initial clathrin coated vesicle (CCV) formation while LRRK2 overexpression inhibits AP2M1 uncoating for entering into a new cycle of CCV formation. Our study also uncovered a novel tissue-specific regulation of AP2M1 phosphorylation by LRRK2. Further, we found LRRK2 phosphorylation on AP2M1 mediates LRRK2-induced neuronal toxicity both in vitro and in vivo. Importantly, AP2M1 phosphorylation levels are elevated in PD patient fibroblasts. Together, our study provides a direct mechanistic link between LRRK2, AP2 and endocytosis in PD pathogenesis.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • The Authors have declared that no conflict of interest exists.

  • The abstract revised.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted June 04, 2020.
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LRRK2 regulates AP2M1 phosphorylation cycles to mediate endocytosis and dopaminergic neurodegeneration
Qinfang Liu, Judith Bautista-Gomez, Daniel A. Higgins, Jianzhong Yu, Yulan Xiong
bioRxiv 2020.05.27.119388; doi: https://doi.org/10.1101/2020.05.27.119388
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LRRK2 regulates AP2M1 phosphorylation cycles to mediate endocytosis and dopaminergic neurodegeneration
Qinfang Liu, Judith Bautista-Gomez, Daniel A. Higgins, Jianzhong Yu, Yulan Xiong
bioRxiv 2020.05.27.119388; doi: https://doi.org/10.1101/2020.05.27.119388

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