Targeted deletion of PAC1 receptors in retinal neurons enhances neuron loss and axonopathy in a model of multiple sclerosis and optic neuritis

Chronic inflammation drives synaptic loss in multiple sclerosis (MS) and is also commonly observed in other neurodegenerative diseases. Clinically approved treatments for MS provide symptomatic relief but fail to halt neurodegeneration and neurological decline. Studies in animal disease models have...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Christina Van, Michael C. Condro, Henly H. Ko, Anh Q. Hoang, Ruoyan Zhu, Kenny Lov, Patrick T. Ricaflanca, Anna L. Diep, Nhat N.M. Nguyen, Gerald S. Lipshutz, Allan MacKenzie-Graham, James A. Waschek
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Multiple sclerosis Optic neuritis Experimental autoimmune encephalomyelitis adcyap1 adcap1r1 PACAP Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/66958102771743ab9562848a5c15b89c
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:66958102771743ab9562848a5c15b89c
record_format	dspace
spelling	oai:doaj.org-article:66958102771743ab9562848a5c15b89c2021-11-12T04:25:56ZTargeted deletion of PAC1 receptors in retinal neurons enhances neuron loss and axonopathy in a model of multiple sclerosis and optic neuritis1095-953X10.1016/j.nbd.2021.105524https://doaj.org/article/66958102771743ab9562848a5c15b89c2021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0969996121002734https://doaj.org/toc/1095-953XChronic inflammation drives synaptic loss in multiple sclerosis (MS) and is also commonly observed in other neurodegenerative diseases. Clinically approved treatments for MS provide symptomatic relief but fail to halt neurodegeneration and neurological decline. Studies in animal disease models have demonstrated that the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP, ADCYAP1) exhibits anti-inflammatory, neuroprotective and regenerative properties. Anti-inflammatory actions appear to be mediated primarily by two receptors, VPAC1 and VPAC2, which also bind vasoactive intestinal peptide (VIP). Pharmacological experiments indicate that another receptor, PAC1 (ADCYAP1R1), which is highly selective for PACAP, provides protection to neurons, although genetic evidence and other mechanistic information is lacking. To determine if PAC1 receptors protect neurons in a cell-autonomous manner, we used adeno-associated virus (AAV2) to deliver Cre recombinase to the retina of mice harboring floxed PAC1 alleles. Mice were then subjected to chronic experimental autoimmune encephalomyelitis (EAE), a disease model that recapitulates major clinical and pathological features of MS and associated optic neuritis. Unexpectedly, deletion of PAC1 in naïve mice resulted in a deficit of retinal ganglionic neurons (RGNs) and their dendrites, suggesting a homeostatic role of PAC1. Moreover, deletion of PAC1 resulted in increased EAE-induced loss of a subpopulation of RGNs purported to be vulnerable in animal models of glaucoma. Increased axonal pathology and increased secondary presence of microglia/macrophages was also prominently seen in the optic nerve. These findings demonstrate that neuronal PAC1 receptors play a homeostatic role in protecting RGNs and directly protects neurons and their axons against neuroinflammatory challenge. Significance statement: Chronic inflammation is a major component of neurodegenerative diseases and plays a central role in multiple sclerosis (MS). Current treatments for MS do not prevent neurodegeneration and/or neurological decline. The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to have anti-inflammatory, neuroprotective and regenerative properties but the cell type- and receptor-specific mechanisms are not clear. To test whether the protective effects of PACAP are direct on the PAC1 receptor subtype on neurons, we delete PAC1 receptors from neurons and investigate neuropathologigical changes in an animal model of MS. The findings demonstrate that PAC1 receptors on neurons play a homeostatic role in maintaining neuron health and can directly protect neurons and their axons during neuroinflammatory disease.Christina VanMichael C. CondroHenly H. KoAnh Q. HoangRuoyan ZhuKenny LovPatrick T. RicaflancaAnna L. DiepNhat N.M. NguyenGerald S. LipshutzAllan MacKenzie-GrahamJames A. WaschekElsevierarticleMultiple sclerosisOptic neuritisExperimental autoimmune encephalomyelitisadcyap1adcap1r1PACAPNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENNeurobiology of Disease, Vol 160, Iss , Pp 105524- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Multiple sclerosis Optic neuritis Experimental autoimmune encephalomyelitis adcyap1 adcap1r1 PACAP Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	Multiple sclerosis Optic neuritis Experimental autoimmune encephalomyelitis adcyap1 adcap1r1 PACAP Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Christina Van Michael C. Condro Henly H. Ko Anh Q. Hoang Ruoyan Zhu Kenny Lov Patrick T. Ricaflanca Anna L. Diep Nhat N.M. Nguyen Gerald S. Lipshutz Allan MacKenzie-Graham James A. Waschek Targeted deletion of PAC1 receptors in retinal neurons enhances neuron loss and axonopathy in a model of multiple sclerosis and optic neuritis
description	Chronic inflammation drives synaptic loss in multiple sclerosis (MS) and is also commonly observed in other neurodegenerative diseases. Clinically approved treatments for MS provide symptomatic relief but fail to halt neurodegeneration and neurological decline. Studies in animal disease models have demonstrated that the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP, ADCYAP1) exhibits anti-inflammatory, neuroprotective and regenerative properties. Anti-inflammatory actions appear to be mediated primarily by two receptors, VPAC1 and VPAC2, which also bind vasoactive intestinal peptide (VIP). Pharmacological experiments indicate that another receptor, PAC1 (ADCYAP1R1), which is highly selective for PACAP, provides protection to neurons, although genetic evidence and other mechanistic information is lacking. To determine if PAC1 receptors protect neurons in a cell-autonomous manner, we used adeno-associated virus (AAV2) to deliver Cre recombinase to the retina of mice harboring floxed PAC1 alleles. Mice were then subjected to chronic experimental autoimmune encephalomyelitis (EAE), a disease model that recapitulates major clinical and pathological features of MS and associated optic neuritis. Unexpectedly, deletion of PAC1 in naïve mice resulted in a deficit of retinal ganglionic neurons (RGNs) and their dendrites, suggesting a homeostatic role of PAC1. Moreover, deletion of PAC1 resulted in increased EAE-induced loss of a subpopulation of RGNs purported to be vulnerable in animal models of glaucoma. Increased axonal pathology and increased secondary presence of microglia/macrophages was also prominently seen in the optic nerve. These findings demonstrate that neuronal PAC1 receptors play a homeostatic role in protecting RGNs and directly protects neurons and their axons against neuroinflammatory challenge. Significance statement: Chronic inflammation is a major component of neurodegenerative diseases and plays a central role in multiple sclerosis (MS). Current treatments for MS do not prevent neurodegeneration and/or neurological decline. The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to have anti-inflammatory, neuroprotective and regenerative properties but the cell type- and receptor-specific mechanisms are not clear. To test whether the protective effects of PACAP are direct on the PAC1 receptor subtype on neurons, we delete PAC1 receptors from neurons and investigate neuropathologigical changes in an animal model of MS. The findings demonstrate that PAC1 receptors on neurons play a homeostatic role in maintaining neuron health and can directly protect neurons and their axons during neuroinflammatory disease.
format	article
author	Christina Van Michael C. Condro Henly H. Ko Anh Q. Hoang Ruoyan Zhu Kenny Lov Patrick T. Ricaflanca Anna L. Diep Nhat N.M. Nguyen Gerald S. Lipshutz Allan MacKenzie-Graham James A. Waschek
author_facet	Christina Van Michael C. Condro Henly H. Ko Anh Q. Hoang Ruoyan Zhu Kenny Lov Patrick T. Ricaflanca Anna L. Diep Nhat N.M. Nguyen Gerald S. Lipshutz Allan MacKenzie-Graham James A. Waschek
author_sort	Christina Van
title	Targeted deletion of PAC1 receptors in retinal neurons enhances neuron loss and axonopathy in a model of multiple sclerosis and optic neuritis
title_short	Targeted deletion of PAC1 receptors in retinal neurons enhances neuron loss and axonopathy in a model of multiple sclerosis and optic neuritis
title_full	Targeted deletion of PAC1 receptors in retinal neurons enhances neuron loss and axonopathy in a model of multiple sclerosis and optic neuritis
title_fullStr	Targeted deletion of PAC1 receptors in retinal neurons enhances neuron loss and axonopathy in a model of multiple sclerosis and optic neuritis
title_full_unstemmed	Targeted deletion of PAC1 receptors in retinal neurons enhances neuron loss and axonopathy in a model of multiple sclerosis and optic neuritis
title_sort	targeted deletion of pac1 receptors in retinal neurons enhances neuron loss and axonopathy in a model of multiple sclerosis and optic neuritis
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/66958102771743ab9562848a5c15b89c
work_keys_str_mv	AT christinavan targeteddeletionofpac1receptorsinretinalneuronsenhancesneuronlossandaxonopathyinamodelofmultiplesclerosisandopticneuritis AT michaelccondro targeteddeletionofpac1receptorsinretinalneuronsenhancesneuronlossandaxonopathyinamodelofmultiplesclerosisandopticneuritis AT henlyhko targeteddeletionofpac1receptorsinretinalneuronsenhancesneuronlossandaxonopathyinamodelofmultiplesclerosisandopticneuritis AT anhqhoang targeteddeletionofpac1receptorsinretinalneuronsenhancesneuronlossandaxonopathyinamodelofmultiplesclerosisandopticneuritis AT ruoyanzhu targeteddeletionofpac1receptorsinretinalneuronsenhancesneuronlossandaxonopathyinamodelofmultiplesclerosisandopticneuritis AT kennylov targeteddeletionofpac1receptorsinretinalneuronsenhancesneuronlossandaxonopathyinamodelofmultiplesclerosisandopticneuritis AT patricktricaflanca targeteddeletionofpac1receptorsinretinalneuronsenhancesneuronlossandaxonopathyinamodelofmultiplesclerosisandopticneuritis AT annaldiep targeteddeletionofpac1receptorsinretinalneuronsenhancesneuronlossandaxonopathyinamodelofmultiplesclerosisandopticneuritis AT nhatnmnguyen targeteddeletionofpac1receptorsinretinalneuronsenhancesneuronlossandaxonopathyinamodelofmultiplesclerosisandopticneuritis AT geraldslipshutz targeteddeletionofpac1receptorsinretinalneuronsenhancesneuronlossandaxonopathyinamodelofmultiplesclerosisandopticneuritis AT allanmackenziegraham targeteddeletionofpac1receptorsinretinalneuronsenhancesneuronlossandaxonopathyinamodelofmultiplesclerosisandopticneuritis AT jamesawaschek targeteddeletionofpac1receptorsinretinalneuronsenhancesneuronlossandaxonopathyinamodelofmultiplesclerosisandopticneuritis
_version_	1718431294039261184

Targeted deletion of PAC1 receptors in retinal neurons enhances neuron loss and axonopathy in a model of multiple sclerosis and optic neuritis

Ejemplares similares