Il-10 signaling reduces survival in mouse models of synucleinopathy

Abstract Parkinson’s disease (PD) and related synucleinopathies are characterized by chronic neuroinflammation leading to the premise that anti-inflammatory therapies could ameliorate synucleinopathy and associated sequelae. To test this idea, we used recombinant adeno-associated viruses (AAV) to ex...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Samuel G. Cockey, Karen N. McFarland, Emily J. Koller, Mieu M. T. Brooks, Elsa Gonzalez De La Cruz, Pedro E. Cruz, Carolina Ceballos-Diaz, Awilda M. Rosario, Yona R. Levites, David R. Borchelt, Todd E. Golde, Benoit I. Giasson, Paramita Chakrabarty
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/7d31e8435b0349f4ac0351ba14562121
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:7d31e8435b0349f4ac0351ba14562121
record_format	dspace
spelling	oai:doaj.org-article:7d31e8435b0349f4ac0351ba145621212021-12-02T11:39:28ZIl-10 signaling reduces survival in mouse models of synucleinopathy10.1038/s41531-021-00169-82373-8057https://doaj.org/article/7d31e8435b0349f4ac0351ba145621212021-03-01T00:00:00Zhttps://doi.org/10.1038/s41531-021-00169-8https://doaj.org/toc/2373-8057Abstract Parkinson’s disease (PD) and related synucleinopathies are characterized by chronic neuroinflammation leading to the premise that anti-inflammatory therapies could ameliorate synucleinopathy and associated sequelae. To test this idea, we used recombinant adeno-associated viruses (AAV) to express the anti-inflammatory cytokine, Interleukin (Il)-10, in Line M83 transgenic mice that expresses the PD-associated A53T mutant human α-synuclein (αSyn). Contrary to our expectations, we observed that intraspinal Il-10 expression initiated at birth upregulated microgliosis and led to early death in homozygous M83+/+ mice. We further observed that Il-10 preconditioning led to reduced lifespan in the hemizygous M83+/− mice injected with preformed αSyn aggregates in hindlimb muscles. To determine the mechanistic basis for these adverse effects, we took advantage of the I87A variant Il-10 (vIl-10) that has predominantly immunosuppressive properties. Sustained intraspinal expression of vIl-10 in preformed αSyn-aggregate seeded M83+/− mice resulted in earlier death, accelerated αSyn pathology, pronounced microgliosis, and increased apoptosis compared to control mice. AAV-vIl-10 expression robustly induced p62 and neuronal LC3B accumulation in these mice, indicating that Il-10 signaling mediated preconditioning of the neuraxis can potentially exacerbate αSyn accumulation through autophagy dysfunction in the neurons. Together, our data demonstrate unexpected adverse effects of both Il-10 and its immunosuppressive variant, vIl-10, in a mouse model of PD, highlighting the pleiotropic functions of immune mediators and their complex role in non-cell autonomous signaling in neurodegenerative proteinopathies.Samuel G. CockeyKaren N. McFarlandEmily J. KollerMieu M. T. BrooksElsa Gonzalez De La CruzPedro E. CruzCarolina Ceballos-DiazAwilda M. RosarioYona R. LevitesDavid R. BorcheltTodd E. GoldeBenoit I. GiassonParamita ChakrabartyNature PortfolioarticleNeurology. Diseases of the nervous systemRC346-429ENnpj Parkinson's Disease, Vol 7, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neurology. Diseases of the nervous system RC346-429
spellingShingle	Neurology. Diseases of the nervous system RC346-429 Samuel G. Cockey Karen N. McFarland Emily J. Koller Mieu M. T. Brooks Elsa Gonzalez De La Cruz Pedro E. Cruz Carolina Ceballos-Diaz Awilda M. Rosario Yona R. Levites David R. Borchelt Todd E. Golde Benoit I. Giasson Paramita Chakrabarty Il-10 signaling reduces survival in mouse models of synucleinopathy
description	Abstract Parkinson’s disease (PD) and related synucleinopathies are characterized by chronic neuroinflammation leading to the premise that anti-inflammatory therapies could ameliorate synucleinopathy and associated sequelae. To test this idea, we used recombinant adeno-associated viruses (AAV) to express the anti-inflammatory cytokine, Interleukin (Il)-10, in Line M83 transgenic mice that expresses the PD-associated A53T mutant human α-synuclein (αSyn). Contrary to our expectations, we observed that intraspinal Il-10 expression initiated at birth upregulated microgliosis and led to early death in homozygous M83+/+ mice. We further observed that Il-10 preconditioning led to reduced lifespan in the hemizygous M83+/− mice injected with preformed αSyn aggregates in hindlimb muscles. To determine the mechanistic basis for these adverse effects, we took advantage of the I87A variant Il-10 (vIl-10) that has predominantly immunosuppressive properties. Sustained intraspinal expression of vIl-10 in preformed αSyn-aggregate seeded M83+/− mice resulted in earlier death, accelerated αSyn pathology, pronounced microgliosis, and increased apoptosis compared to control mice. AAV-vIl-10 expression robustly induced p62 and neuronal LC3B accumulation in these mice, indicating that Il-10 signaling mediated preconditioning of the neuraxis can potentially exacerbate αSyn accumulation through autophagy dysfunction in the neurons. Together, our data demonstrate unexpected adverse effects of both Il-10 and its immunosuppressive variant, vIl-10, in a mouse model of PD, highlighting the pleiotropic functions of immune mediators and their complex role in non-cell autonomous signaling in neurodegenerative proteinopathies.
format	article
author	Samuel G. Cockey Karen N. McFarland Emily J. Koller Mieu M. T. Brooks Elsa Gonzalez De La Cruz Pedro E. Cruz Carolina Ceballos-Diaz Awilda M. Rosario Yona R. Levites David R. Borchelt Todd E. Golde Benoit I. Giasson Paramita Chakrabarty
author_facet	Samuel G. Cockey Karen N. McFarland Emily J. Koller Mieu M. T. Brooks Elsa Gonzalez De La Cruz Pedro E. Cruz Carolina Ceballos-Diaz Awilda M. Rosario Yona R. Levites David R. Borchelt Todd E. Golde Benoit I. Giasson Paramita Chakrabarty
author_sort	Samuel G. Cockey
title	Il-10 signaling reduces survival in mouse models of synucleinopathy
title_short	Il-10 signaling reduces survival in mouse models of synucleinopathy
title_full	Il-10 signaling reduces survival in mouse models of synucleinopathy
title_fullStr	Il-10 signaling reduces survival in mouse models of synucleinopathy
title_full_unstemmed	Il-10 signaling reduces survival in mouse models of synucleinopathy
title_sort	il-10 signaling reduces survival in mouse models of synucleinopathy
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/7d31e8435b0349f4ac0351ba14562121
work_keys_str_mv	AT samuelgcockey il10signalingreducessurvivalinmousemodelsofsynucleinopathy AT karennmcfarland il10signalingreducessurvivalinmousemodelsofsynucleinopathy AT emilyjkoller il10signalingreducessurvivalinmousemodelsofsynucleinopathy AT mieumtbrooks il10signalingreducessurvivalinmousemodelsofsynucleinopathy AT elsagonzalezdelacruz il10signalingreducessurvivalinmousemodelsofsynucleinopathy AT pedroecruz il10signalingreducessurvivalinmousemodelsofsynucleinopathy AT carolinaceballosdiaz il10signalingreducessurvivalinmousemodelsofsynucleinopathy AT awildamrosario il10signalingreducessurvivalinmousemodelsofsynucleinopathy AT yonarlevites il10signalingreducessurvivalinmousemodelsofsynucleinopathy AT davidrborchelt il10signalingreducessurvivalinmousemodelsofsynucleinopathy AT toddegolde il10signalingreducessurvivalinmousemodelsofsynucleinopathy AT benoitigiasson il10signalingreducessurvivalinmousemodelsofsynucleinopathy AT paramitachakrabarty il10signalingreducessurvivalinmousemodelsofsynucleinopathy
_version_	1718395708655009792

Il-10 signaling reduces survival in mouse models of synucleinopathy

Ejemplares similares