Abstract

Activation of microglia by classical inflammatory mediators can convert astrocytes into a neurotoxic A1 phenotype in a variety of neurological diseases1,2. Development of agents that could inhibit the formation of A1 reactive astrocytes could be used to treat these diseases for which there are no disease-modifying therapies. Glucagon-like peptide-1 receptor (GLP1R) agonists have been indicated as potential neuroprotective agents for neurologic disorders such as Alzheimer’s disease and Parkinson’s disease3,4,5,6,7,8,9,10,11,12,13. The mechanisms by which GLP1R agonists are neuroprotective are not known. Here we show that a potent, brain-penetrant long-acting GLP1R agonist, NLY01, protects against the loss of dopaminergic neurons and behavioral deficits in the α-synuclein preformed fibril (α-syn PFF) mouse model of sporadic Parkinson’s disease14,15. NLY01 also prolongs the life and reduces the behavioral deficits and neuropathological abnormalities in the human A53T α-synuclein (hA53T) transgenic mouse model of α-synucleinopathy-induced neurodegeneration16. We found that NLY01 is a potent GLP1R agonist with favorable properties that is neuroprotective through the direct prevention of microglial-mediated conversion of astrocytes to an A1 neurotoxic phenotype. In light of its favorable properties, NLY01 should be evaluated in the treatment of Parkinson’s disease and related neurologic disorders characterized by microglial activation.

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Acknowledgements

All relevant ethical regulations were followed. This work was supported by grants from the NIH/NINDS NS38377 (H.S.K., V.L.D. and T.M.D.), NIH/NINDS NS082205 and NS098006 (H.S.K.), Maryland Stem Cell Research Foundation 2012-MSCRFE-0059 (H.S.K.), the JPB Foundation (T.M.D.), NIH/National Institute on Aging grant 1K01AG056841-01(X.M.), the American Parkinson Disease Association (APDA) Research Grant Awards (X.M.) and the National Research Foundation of Korea NRF-2016R1D1A1B03934847 (D.H.N.). We acknowledge the joint participation by the Adrienne Helis Malvin Medical Research Foundation and the Diana Helis Henry Medical Research Foundation through their direct engagement in the continuous active conduct of medical research in conjunction with The Johns Hopkins Hospital and the Johns Hopkins University School of Medicine and the Foundation’s Parkinson’s Disease Programs M-1 (T.M.D. and V.L.D.), M-2 (T.M.D. and V.L.D.), H-2014 (T.M.D.), M-2014 (H.S.K., T.M.D. and V.L.D.), H-1 (H.S.K.), H-2013 (H.S.K.). T.M.D. is the Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases. We thank Neuraly Inc. for providing NLY01.

Author information

Author notes

  1. These authors contributed equally: Seung Pil Yun, Tae-In Kam.

Affiliations

  1. Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • Seung Pil Yun
    • , Tae-In Kam
    • , Nikhil Panicker
    • , SangMin Kim
    • , Seung-Hwan Kwon
    • , Senthilkumar S. Karuppagounder
    • , Hyejin Park
    • , Sangjune Kim
    • , Nayeon Oh
    • , Nayoung Alice Kim
    • , Saebom Lee
    • , Saurav Brahmachari
    • , Xiaobo Mao
    • , Manoj Kumar
    • , Daniel An
    • , Sung-Ung Kang
    • , Donghoon Kim
    • , Valina L. Dawson
    • , Ted M. Dawson
    •  & Han Seok Ko
  2. Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • Seung Pil Yun
    • , Tae-In Kam
    • , Nikhil Panicker
    • , SangMin Kim
    • , Seung-Hwan Kwon
    • , Senthilkumar S. Karuppagounder
    • , Hyejin Park
    • , Sangjune Kim
    • , Nayeon Oh
    • , Nayoung Alice Kim
    • , Saebom Lee
    • , Saurav Brahmachari
    • , Xiaobo Mao
    • , Manoj Kumar
    • , Daniel An
    • , Sung-Ung Kang
    • , Donghoon Kim
    • , Zoltan Mari
    • , Valina L. Dawson
    • , Ted M. Dawson
    •  & Han Seok Ko
  3. Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, USA

    • Seung Pil Yun
    • , Senthilkumar S. Karuppagounder
    • , Saurav Brahmachari
    • , Xiaobo Mao
    • , Valina L. Dawson
    • , Ted M. Dawson
    •  & Han Seok Ko
  4. The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • Yumin Oh
    • , Jong-Sung Park
    • , Yong Joo Park
    •  & Seulki Lee
  5. The Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • Yumin Oh
    • , Jong-Sung Park
    • , Yong Joo Park
    •  & Seulki Lee
  6. Department of Pharmacology and Toxicology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA

    • Jun Hee Lee
  7. Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, South Korea

    • Yunjong Lee
  8. College of Pharmacy, Sungkyunkwan University, Suwon, South Korea

    • Kang Choon Lee
  9. College of Pharmacy, Chung-Ang University, Seoul, South Korea

    • Dong Hee Na
  10. Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • Donghoon Kim
    •  & Valina L. Dawson
  11. Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • Donghoon Kim
    • , Valina L. Dawson
    •  & Ted M. Dawson
  12. Soonchunhyang Medical Science Research Institute, Soonchunhyang University, Seoul Hospital, Seoul, South Korea

    • Sang Hun Lee
  13. Neuraly Inc, Baltimore, MD, USA

    • Viktor V. Roschke
  14. Department of Neurobiology, Stanford University, School of Medicine, Stanford, CA, USA

    • Shane A. Liddelow
    •  & Ben A. Barres
  15. Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • Ted M. Dawson
  16. Diana Helis Henry Medical Research Foundation, New Orleans, LA, USA

    • Ted M. Dawson
    •  & Han Seok Ko

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Contributions

S.P.Y. and T.-I.K. designed the majority of the experiments, performed the experiments, analyzed data and wrote the manuscript. N.P., S.M.K., Y.O., J.-S.P., S.-H.K., S.-U.K. and D.K. performed experiments and data interpretation. Y.J.P. injected NLY01 into mice. S.S.K. performed HPLC analysis. H.P., S.K., N.O., N.A.K., Sa.L., J.H.L., M.K. and D.A. performed sample preparation and helped with experiments. S.B. and X.M. provided and managed mice and PFF, and helped with data interpretation. K.C.L. and D.H.N. provided and made NLY01. V.V.R. performed mouse pharmacokinetic experiments and data analysis. Y.L., S.H.L., S.A.L. and B.A.B. preformed manuscript writing, review and editing. Z.M. provided human postmortem brain samples. V.L.D., Se.L., T.M.D. and H.S.K. supervised the project, formulated the hypothesis, designed experiments, analyzed data and wrote the manuscript.

Competing interests

Z.M., V.L.D., Se.L., T.M.D. and H.S.K are co-founders of Neuraly Inc. and hold ownership equity in the company. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. V.V.R. is the CSO of Neuraly Inc.

Corresponding authors

Correspondence to Seulki Lee or Ted M. Dawson or Han Seok Ko.

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https://doi.org/10.1038/s41591-018-0051-5

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