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 Karuppagounder, Hyejin Park, Sangjune Kim, Nayeon Oh, Nayoung Alice Kim, Saebom Lee, Saurav Brahmachari, Xiaobo Mao, Jun Hee Lee, Manoj Kumar, Daniel An, SungUng 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 Dawson, Seulki Lee, Ted M Dawson, Hanseok 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

Fingerprint

Microglia
Astrocytes
Parkinson Disease
Synucleins
Nervous System Diseases
Phenotype
Dopaminergic Neurons
Neuroprotective Agents
Transgenic Mice
Chemical activation
Alzheimer Disease
Glucagon-Like Peptide-1 Receptor
Brain
Neurons
Therapeutics

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson's disease. / Yun, Seung Pil; Kam, Tae-In; Panicker, Nikhil; Kim, Sangmin; Oh, Yumin; Park, Jong Sung; Kwon, Seung Hwan; Park, Yong Joo; Karuppagounder, Senthilkumar; Park, Hyejin; Kim, Sangjune; Oh, Nayeon; Kim, Nayoung Alice; Lee, Saebom; Brahmachari, Saurav; Mao, Xiaobo; Lee, Jun Hee; Kumar, Manoj; An, Daniel; Kang, SungUng; Lee, Yunjong; Lee, Kang Choon; Na, Dong Hee; Kim, Donghoon; Lee, Sang Hun; Roschke, Viktor V.; Liddelow, Shane A.; Mari, Zoltan; Barres, Ben A.; Dawson, Valina; Lee, Seulki; Dawson, Ted M; Ko, Hanseok Seok.

In: Nature Medicine, Vol. 24, No. 7, 01.07.2018, p. 931-938.

Research output: Contribution to journalArticle

Yun, SP, Kam, T-I, Panicker, N, Kim, S, Oh, Y, Park, JS, Kwon, SH, Park, YJ, Karuppagounder, S, Park, H, Kim, S, Oh, N, Kim, NA, Lee, S, Brahmachari, S, Mao, X, Lee, JH, Kumar, M, An, D, Kang, S, Lee, Y, Lee, KC, Na, DH, Kim, D, Lee, SH, Roschke, VV, Liddelow, SA, Mari, Z, Barres, BA, Dawson, V, Lee, S, Dawson, TM & Ko, HS 2018, 'Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson's disease', Nature Medicine, vol. 24, no. 7, pp. 931-938. https://doi.org/10.1038/s41591-018-0051-5
Yun, Seung Pil ; Kam, Tae-In ; Panicker, Nikhil ; Kim, Sangmin ; Oh, Yumin ; Park, Jong Sung ; Kwon, Seung Hwan ; Park, Yong Joo ; Karuppagounder, Senthilkumar ; Park, Hyejin ; Kim, Sangjune ; Oh, Nayeon ; Kim, Nayoung Alice ; Lee, Saebom ; Brahmachari, Saurav ; Mao, Xiaobo ; Lee, Jun Hee ; Kumar, Manoj ; An, Daniel ; Kang, SungUng ; Lee, Yunjong ; Lee, Kang Choon ; Na, Dong Hee ; Kim, Donghoon ; Lee, Sang Hun ; Roschke, Viktor V. ; Liddelow, Shane A. ; Mari, Zoltan ; Barres, Ben A. ; Dawson, Valina ; Lee, Seulki ; Dawson, Ted M ; Ko, Hanseok Seok. / Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson's disease. In: Nature Medicine. 2018 ; Vol. 24, No. 7. pp. 931-938.
@article{9f13e7bb6afa4e0cb610405fb935b54e,
title = "Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson's disease",
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.",
author = "Yun, {Seung Pil} and Tae-In Kam and Nikhil Panicker and Sangmin Kim and Yumin Oh and Park, {Jong Sung} and Kwon, {Seung Hwan} and Park, {Yong Joo} and Senthilkumar Karuppagounder and Hyejin Park and Sangjune Kim and Nayeon Oh and Kim, {Nayoung Alice} and Saebom Lee and Saurav Brahmachari and Xiaobo Mao and Lee, {Jun Hee} and Manoj Kumar and Daniel An and SungUng Kang and Yunjong Lee and Lee, {Kang Choon} and Na, {Dong Hee} and Donghoon Kim and Lee, {Sang Hun} and Roschke, {Viktor V.} and Liddelow, {Shane A.} and Zoltan Mari and Barres, {Ben A.} and Valina Dawson and Seulki Lee and Dawson, {Ted M} and Ko, {Hanseok Seok}",
year = "2018",
month = "7",
day = "1",
doi = "10.1038/s41591-018-0051-5",
language = "English (US)",
volume = "24",
pages = "931--938",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "7",

}

TY - JOUR

T1 - Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson's disease

AU - Yun, Seung Pil

AU - Kam, Tae-In

AU - Panicker, Nikhil

AU - Kim, Sangmin

AU - Oh, Yumin

AU - Park, Jong Sung

AU - Kwon, Seung Hwan

AU - Park, Yong Joo

AU - Karuppagounder, Senthilkumar

AU - Park, Hyejin

AU - Kim, Sangjune

AU - Oh, Nayeon

AU - Kim, Nayoung Alice

AU - Lee, Saebom

AU - Brahmachari, Saurav

AU - Mao, Xiaobo

AU - Lee, Jun Hee

AU - Kumar, Manoj

AU - An, Daniel

AU - Kang, SungUng

AU - Lee, Yunjong

AU - Lee, Kang Choon

AU - Na, Dong Hee

AU - Kim, Donghoon

AU - Lee, Sang Hun

AU - Roschke, Viktor V.

AU - Liddelow, Shane A.

AU - Mari, Zoltan

AU - Barres, Ben A.

AU - Dawson, Valina

AU - Lee, Seulki

AU - Dawson, Ted M

AU - Ko, Hanseok Seok

PY - 2018/7/1

Y1 - 2018/7/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85048318201&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85048318201&partnerID=8YFLogxK

U2 - 10.1038/s41591-018-0051-5

DO - 10.1038/s41591-018-0051-5

M3 - Article

C2 - 29892066

AN - SCOPUS:85048318201

VL - 24

SP - 931

EP - 938

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 7

ER -