Early auto‐immune targeting of photoreceptor ribbon synapses in mouse models of multiple sclerosis. Issue 11 (28th September 2018)

• Record Type: Journal Article
• Authors: Dembla, Mayur; Kesharwani, Ajay; Natarajan, Sivaraman; Fecher‐Trost, Claudia; Fairless, Richard; Williams, Sarah K; Flockerzi, Veit; Diem, Ricarda; Schwarz, Karin; Schmitz, Frank
• Is Part Of: EMBO molecular medicine. Volume 10:Issue 11(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-09-28
• Subjects: CASPR1 -- multiple sclerosis -- retina -- ribbon synapse -- RIBEYE; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.201808926
• Languages: English
• ISSNs: 1757-4676

Abstract

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. Synopsis: The primary events that lead to optic neuritis (ON) in multiple sclerosis (MS) remain unclear. The paranodal protein CASPR1 is expressed at retinal ribbon synapses and is strongly affected in animal models of MS/ON. Synaptic alterations within the retina precede demyelination in the optic nerve. The paranodal adhesion proteins CASPR1 and CNTN1 are highly enriched at retinal ribbon synapses. Expression of both CASPR1 and CNTN1 is decreased in mouse models of ON before the onset of clinical symptoms. Retinal ribbon synapses are targeted by an auto‐reactive immune system in the pre‐clinical phase of experimental autoimmune encephalomyelitis before morphologically visible changes in the optic nerve occur. Altered synaptic vesicle cycling and altered visual behavior precede demyelination of the optic nerve. Abstract : The primary events that lead to optic neuritis (ON) in multiple sclerosis (MS) remain unclear. The paranodal protein CASPR1 is expressed at retinal ribbon synapses and is strongly affected in animal models of MS/ON. Synaptic alterations within the retina precede demyelination in the optic nerve.