Aplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein

Xiaobo Mao; Hao Gu; Donghoon Kim; Yasuyoshi Kimura; Ning Wang; Enquan Xu; Ramhari Kumbhar; Xiaotian Ming; Haibo Wang; Chan Chen; Shengnan Zhang; Chunyu Jia; Yuqing Liu; Hetao Bian; Senthilkumar S Karuppagounder; Fatih Akkentli; Qi Chen; Longgang Jia; Heehong Hwang; Su Hyun Lee; Xiyu Ke; Michael Chang; Amanda Li; Jun Yang; Cyrus Rastegar; Manjari Sriparna; Preston Ge; Saurav Brahmachari; Sangjune Kim; Shu Zhang; Yasushi Shimoda; Martina Saar; Haiqing Liu; Sin Ho Kweon; Mingyao Ying; Creg J Workman; Dario A A Vignali; Ulrike C Muller; Cong Liu; Han Seok Ko; Valina L Dawson; Ted M Dawson

doi:10.1038/s41467-024-49016-3

Aplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein

Nat Commun. 2024 May 31;15(1):4663. doi: 10.1038/s41467-024-49016-3.

Authors

Xiaobo Mao^#^{1

2

3}, Hao Gu^#^{4

5

6

7}, Donghoon Kim^#^{4

5

8}, Yasuyoshi Kimura^{4

5}, Ning Wang^{4

5}, Enquan Xu^{4

5}, Ramhari Kumbhar^{4

5

9}, Xiaotian Ming^{4

5}, Haibo Wang^{4

5}, Chan Chen^{4

5

10}, Shengnan Zhang¹¹, Chunyu Jia^{11

12}, Yuqing Liu^{4

5}, Hetao Bian^{4

5}, Senthilkumar S Karuppagounder^{4

5}, Fatih Akkentli^{4

5

9}, Qi Chen^{4

5}, Longgang Jia^{4

5}, Heehong Hwang^{4

5}, Su Hyun Lee^{4

5}, Xiyu Ke^{13

14}, Michael Chang^{4

5}, Amanda Li^{4

5}, Jun Yang^{4

5}, Cyrus Rastegar^{4

5}, Manjari Sriparna^{4

5}, Preston Ge^{4

5

15

16

17}, Saurav Brahmachari^{4

5}, Sangjune Kim^{4

5

18}, Shu Zhang^{4

5}, Yasushi Shimoda¹⁹, Martina Saar²⁰, Haiqing Liu^{4

5

21}, Sin Ho Kweon^{4

5}, Mingyao Ying^{5

22}, Creg J Workman²³, Dario A A Vignali^{23

24}, Ulrike C Muller²⁰, Cong Liu¹¹, Han Seok Ko^{25

26

27}, Valina L Dawson^{28

29

30

31

32}, Ted M Dawson^{33

34

35

36

37}

Affiliations

¹ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. [email protected].
² Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. [email protected].
³ Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, 70130-2685, USA. [email protected].
⁴ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
⁵ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
⁶ Department of Neurology, Nanjing Brain Hospital, Nanjing, Jiangsu, 210029, PR China.
⁷ Medical College, Yangzhou University, Yangzhou, Jiangsu, 225001, PR China.
⁸ Department of Pharmacology, College of Medicine, Dong-A University, 32 Daesin Gongwwon-ro, Seo-gu, Busan, 49201, Republic of Korea.
⁹ Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, 70130-2685, USA.
¹⁰ Department of Anesthesiology, West China Hospital, Sichuan University. The Research Units of West China (2018RU012)-Chinese Academy of Medical Sciences, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, PR China.
¹¹ Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 26 Qiuyue Road, Shanghai, 201210, China.
¹² University of the Chinese Academy of Sciences, 19 A Yuquan Road, Shijingshan District, Beijing, 100049, China.
¹³ Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, 21218, USA.
¹⁴ Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.
¹⁵ Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
¹⁶ Picower Institute for Learning and Memory, Cambridge, MA, 02139, USA.
¹⁷ Harvard-MIT MD/PhD Program, Harvard Medical School, Boston, MA, 02115, USA.
¹⁸ Department of Biological Science and Biotechnology, Chungbuk National University, Cheongju, Chungbuk, 28644, Republic of Korea.
¹⁹ Department of Bioengineering, Nagaoka University of Technology, 1603-1 Kamitomiokamachi, Nagaoka, Niigata, 940-2188, Japan.
²⁰ Institute for Pharmacy and Molecular Biotechnology IPMB, Department of Functional Genomics, University of Heidelberg, Im Neuenheimer Feld 364, 69120, Heidelberg, Germany.
²¹ Department of Physiology, School of Basic Medical Sciences (Institute of Basic Medical Sciences), Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250000, China.
²² Hugo W. Moser Research Institute at Kennedy Krieger, 707 North Broadway, Baltimore, MD, 21205, USA.
²³ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA.
²⁴ Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, 15232, USA.
²⁵ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. [email protected].
²⁶ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. [email protected].
²⁷ Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, 70130-2685, USA. [email protected].
²⁸ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. [email protected].
²⁹ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. [email protected].
³⁰ Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, 70130-2685, USA. [email protected].
³¹ Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. [email protected].
³² Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. [email protected].
³³ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. [email protected].
³⁴ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. [email protected].
³⁵ Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, 70130-2685, USA. [email protected].
³⁶ Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. [email protected].
³⁷ Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. [email protected].

^# Contributed equally.

Abstract

Pathologic α-synuclein (α-syn) spreads from cell-to-cell, in part, through binding to the lymphocyte-activation gene 3 (Lag3). Here we report that amyloid β precursor-like protein 1 (Aplp1) interacts with Lag3 that facilitates the binding, internalization, transmission, and toxicity of pathologic α-syn. Deletion of both Aplp1 and Lag3 eliminates the loss of dopaminergic neurons and the accompanying behavioral deficits induced by α-syn preformed fibrils (PFF). Anti-Lag3 prevents the internalization of α-syn PFF by disrupting the interaction of Aplp1 and Lag3, and blocks the neurodegeneration induced by α-syn PFF in vivo. The identification of Aplp1 and the interplay with Lag3 for α-syn PFF induced pathology deepens our insight about molecular mechanisms of cell-to-cell transmission of pathologic α-syn and provides additional targets for therapeutic strategies aimed at preventing neurodegeneration in Parkinson's disease and related α-synucleinopathies.

MeSH terms

Amyloid beta-Protein Precursor / genetics
Amyloid beta-Protein Precursor / metabolism
Animals
Antigens, CD / genetics
Antigens, CD / metabolism
Dopaminergic Neurons / metabolism
Dopaminergic Neurons / pathology
Female
Humans
Lymphocyte Activation Gene 3 Protein*
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Parkinson Disease / genetics
Parkinson Disease / metabolism
Parkinson Disease / pathology
Protein Binding
alpha-Synuclein* / genetics
alpha-Synuclein* / metabolism

Substances

alpha-Synuclein
Amyloid beta-Protein Precursor
Antigens, CD
Lag3 protein, human
Lymphocyte Activation Gene 3 Protein
APLP1 protein, human

Abstract

MeSH terms

Substances

Grants and funding