Early auto‐immune targeting of photoreceptor ribbon synapses in mouse models of multiple sclerosis
Abstract Optic neuritis is one of the first manifestations of multiple sclerosis. Its pathogenesis is incompletely understood, but considered to be initiated by an auto‐immune response directed against myelin sheaths of the optic nerve. Here, we demonstrate in two frequently used and well‐validated...
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doaj-7372cd2bdb174bcbac029be8963c4d0f2021-08-02T02:50:00ZengWileyEMBO Molecular Medicine1757-46761757-46842018-11-011011n/an/a10.15252/emmm.201808926Early auto‐immune targeting of photoreceptor ribbon synapses in mouse models of multiple sclerosisMayur Dembla0Ajay Kesharwani1Sivaraman Natarajan2Claudia Fecher‐Trost3Richard Fairless4Sarah K Williams5Veit Flockerzi6Ricarda Diem7Karin Schwarz8Frank Schmitz9Department of Neuroanatomy Institute of Anatomy and Cell Biology Medical School Saarland University Homburg GermanyDepartment of Neuroanatomy Institute of Anatomy and Cell Biology Medical School Saarland University Homburg GermanyDepartment of Neuroanatomy Institute of Anatomy and Cell Biology Medical School Saarland University Homburg GermanyInstitute of Experimental and Clinical Pharmacology and Toxicology Medical School Saarland University Homburg GermanyDepartment of Neurology University Clinic Heidelberg Heidelberg GermanyDepartment of Neurology University Clinic Heidelberg Heidelberg GermanyInstitute of Experimental and Clinical Pharmacology and Toxicology Medical School Saarland University Homburg GermanyDepartment of Neurology University Clinic Heidelberg Heidelberg GermanyDepartment of Neuroanatomy Institute of Anatomy and Cell Biology Medical School Saarland University Homburg GermanyDepartment of Neuroanatomy Institute of Anatomy and Cell Biology Medical School Saarland University Homburg GermanyAbstract Optic neuritis is one of the first manifestations of multiple sclerosis. Its pathogenesis is incompletely understood, but considered to be initiated by an auto‐immune response directed against myelin sheaths of the optic nerve. Here, we demonstrate in two frequently used and well‐validated mouse models of optic neuritis that ribbon synapses in the myelin‐free retina are targeted by an auto‐reactive immune system even before alterations in the optic nerve have developed. The auto‐immune response is directed against two adhesion proteins (CASPR1/CNTN1) that are present both in the paranodal region of myelinated nerves as well as at retinal ribbon synapses. This occurs in parallel with altered synaptic vesicle cycling in retinal ribbon synapses and altered visual behavior before the onset of optic nerve demyelination. These findings indicate that early synaptic dysfunctions in the retina contribute to the pathology of optic neuritis in multiple sclerosis.https://doi.org/10.15252/emmm.201808926CASPR1multiple sclerosisretinaribbon synapseRIBEYE |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Mayur Dembla Ajay Kesharwani Sivaraman Natarajan Claudia Fecher‐Trost Richard Fairless Sarah K Williams Veit Flockerzi Ricarda Diem Karin Schwarz Frank Schmitz |
spellingShingle |
Mayur Dembla Ajay Kesharwani Sivaraman Natarajan Claudia Fecher‐Trost Richard Fairless Sarah K Williams Veit Flockerzi Ricarda Diem Karin Schwarz Frank Schmitz Early auto‐immune targeting of photoreceptor ribbon synapses in mouse models of multiple sclerosis EMBO Molecular Medicine CASPR1 multiple sclerosis retina ribbon synapse RIBEYE |
author_facet |
Mayur Dembla Ajay Kesharwani Sivaraman Natarajan Claudia Fecher‐Trost Richard Fairless Sarah K Williams Veit Flockerzi Ricarda Diem Karin Schwarz Frank Schmitz |
author_sort |
Mayur Dembla |
title |
Early auto‐immune targeting of photoreceptor ribbon synapses in mouse models of multiple sclerosis |
title_short |
Early auto‐immune targeting of photoreceptor ribbon synapses in mouse models of multiple sclerosis |
title_full |
Early auto‐immune targeting of photoreceptor ribbon synapses in mouse models of multiple sclerosis |
title_fullStr |
Early auto‐immune targeting of photoreceptor ribbon synapses in mouse models of multiple sclerosis |
title_full_unstemmed |
Early auto‐immune targeting of photoreceptor ribbon synapses in mouse models of multiple sclerosis |
title_sort |
early auto‐immune targeting of photoreceptor ribbon synapses in mouse models of multiple sclerosis |
publisher |
Wiley |
series |
EMBO Molecular Medicine |
issn |
1757-4676 1757-4684 |
publishDate |
2018-11-01 |
description |
Abstract Optic neuritis is one of the first manifestations of multiple sclerosis. Its pathogenesis is incompletely understood, but considered to be initiated by an auto‐immune response directed against myelin sheaths of the optic nerve. Here, we demonstrate in two frequently used and well‐validated mouse models of optic neuritis that ribbon synapses in the myelin‐free retina are targeted by an auto‐reactive immune system even before alterations in the optic nerve have developed. The auto‐immune response is directed against two adhesion proteins (CASPR1/CNTN1) that are present both in the paranodal region of myelinated nerves as well as at retinal ribbon synapses. This occurs in parallel with altered synaptic vesicle cycling in retinal ribbon synapses and altered visual behavior before the onset of optic nerve demyelination. These findings indicate that early synaptic dysfunctions in the retina contribute to the pathology of optic neuritis in multiple sclerosis. |
topic |
CASPR1 multiple sclerosis retina ribbon synapse RIBEYE |
url |
https://doi.org/10.15252/emmm.201808926 |
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