Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson's disease

Seung Pil Yun, Tae In Kam, Nikhil Panicker, Sangmin Kim, Yumin Oh, Jong Sung Park, Seung Hwan Kwon, Yong Joo Park, Senthilkumar S. Karuppagounder, Hyejin Park, Sangjune Kim, Nayeon Oh, Nayoung Alice Kim, Saebom Lee, Saurav Brahmachari, Xiaobo Mao, Jun Hee Lee, Manoj Kumar, Daniel An, Sung Ung KangYunjong Lee, Kang Choon Lee, Dong Hee Na, Donghoon Kim, Sang Hun Lee, Viktor V. Roschke, Shane A. Liddelow, Zoltan Mari, Ben A. Barres, Valina L. Dawson, Seulki Lee, Ted M. Dawson, Han Seok Ko

Research output: Contribution to journalArticle

Abstract

Activation of microglia by classical inflammatory mediators can convert astrocytes into a neurotoxic A1 phenotype in a variety of neurological diseases 1,2 . 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 disease 3-13 . 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 disease 14,15 . 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 neurodegeneration 16 . 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.

Original languageEnglish (US)
Pages (from-to)931-938
Number of pages8
JournalNature medicine
Volume24
Issue number7
DOIs
StatePublished - Jul 1 2018

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Yun, S. P., Kam, T. I., Panicker, N., Kim, S., Oh, Y., Park, J. S., Kwon, S. H., Park, Y. J., Karuppagounder, S. S., Park, H., Kim, S., Oh, N., Kim, N. A., Lee, S., Brahmachari, S., Mao, X., Lee, J. H., Kumar, M., An, D., ... Ko, H. S. (2018). Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson's disease. Nature medicine, 24(7), 931-938. https://doi.org/10.1038/s41591-018-0051-5