Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3

Xiaobo Mao; Michael Tianhao Ou; Senthilkumar S Karuppagounder; Tae-In Kam; Xiling Yin; Yulan Xiong; Preston Ge; George Essien Umanah; Saurav Brahmachari; Joo-Ho Shin; Ho Chul Kang; Jianmin Zhang; Jinchong Xu; Rong Chen; Hyejin Park; Shaida A Andrabi; Sung Ung Kang; Rafaella Araújo Gonçalves; Yu Liang; Shu Zhang; Chen Qi; Sharon Lam; James A Keiler; Joel Tyson; Donghoon Kim; Nikhil Panicker; Seung Pil Yun; Creg J Workman; Dario A A Vignali; Valina L Dawson; Han Seok Ko; Ted M Dawson

doi:10.1126/science.aah3374

Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3

Science. 2016 Sep 30;353(6307):aah3374. doi: 10.1126/science.aah3374.

Authors

Xiaobo Mao¹, Michael Tianhao Ou², Senthilkumar S Karuppagounder¹, Tae-In Kam¹, Xiling Yin¹, Yulan Xiong¹, Preston Ge², George Essien Umanah¹, Saurav Brahmachari¹, Joo-Ho Shin³, Ho Chul Kang⁴, Jianmin Zhang², Jinchong Xu¹, Rong Chen¹, Hyejin Park¹, Shaida A Andrabi¹, Sung Ung Kang¹, Rafaella Araújo Gonçalves², Yu Liang², Shu Zhang², Chen Qi⁵, Sharon Lam², James A Keiler², Joel Tyson⁶, Donghoon Kim², Nikhil Panicker¹, Seung Pil Yun¹, Creg J Workman⁷, Dario A A Vignali⁸, Valina L Dawson⁹, Han Seok Ko¹⁰, Ted M Dawson¹¹

Affiliations

¹ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
² Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 440-746, South Korea.
⁴ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Physiology, Ajou University School of Medicine, Suwon 443-721, South Korea.
⁵ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Xin Hua Hospital affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China.
⁶ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Johns Hopkins Institute for NanoBio Technology, Johns Hopkins University, Baltimore, MD 21218, USA.
⁷ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
⁸ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA.
⁹ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA. Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. tdawson@jhmi.edu hko3@jhmi.edu vdawson1@jhmi.edu.
¹⁰ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA. tdawson@jhmi.edu hko3@jhmi.edu vdawson1@jhmi.edu.
¹¹ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Johns Hopkins Institute for NanoBio Technology, Johns Hopkins University, Baltimore, MD 21218, USA. Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. tdawson@jhmi.edu hko3@jhmi.edu vdawson1@jhmi.edu.

Abstract

Emerging evidence indicates that the pathogenesis of Parkinson's disease (PD) may be due to cell-to-cell transmission of misfolded preformed fibrils (PFF) of α-synuclein (α-syn). The mechanism by which α-syn PFF spreads from neuron to neuron is not known. Here, we show that LAG3 (lymphocyte-activation gene 3) binds α-syn PFF with high affinity (dissociation constant = 77 nanomolar), whereas the α-syn monomer exhibited minimal binding. α-Syn-biotin PFF binding to LAG3 initiated α-syn PFF endocytosis, transmission, and toxicity. Lack of LAG3 substantially delayed α-syn PFF-induced loss of dopamine neurons, as well as biochemical and behavioral deficits in vivo. The identification of LAG3 as a receptor that binds α-syn PFF provides a target for developing therapeutics designed to slow the progression of PD and related α-synucleinopathies.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, CD / metabolism*
Dopaminergic Neurons / metabolism
Endocytosis
Humans
Lymphocyte Activation Gene 3 Protein
Mice
Mice, Transgenic
Parkinson Disease / metabolism*
Protein Binding
Protein Transport
alpha-Synuclein / genetics
alpha-Synuclein / metabolism*

Substances

Antigens, CD
SNCA protein, human
alpha-Synuclein
Lymphocyte Activation Gene 3 Protein

Abstract

Publication types

MeSH terms

Substances

Grants and funding