Synapsin-antibodies in psychiatric and neurological disorders: Prevalence and clinical findings

Höltje, Markus; Mertens, Robert; Schou, Morten Brix; Sæther, Sverre Georg; Kochova, Elena; Jarius, Sven; Prüß, Harald; Komorowski, Lars; Probst, Christian; Paul, Friedemann; Bellmann‐Strobl, Judith; Gitler, Daniel; Benfenati, Fabio; Piepgras, Johannes; Ahnert‐Hilger, Gudrun; Ruprecht, Klemens

doi:10.1016/j.bbi.2017.07.011

Cited by 16 publications

(38 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is expressed in the nervous system of vertebrates and is crucial for neuronal development and neurotransmission [68]. Intriguingly, autoantibodies to human synapsin Ia and Ib are detectable in sera from patients with different psychiatric and neurological disorders [69]. Synapsin regulates Fyn-dependent brain-derived neurotrophic factor (BDNF)-mediated synaptic potentiation and neurite outgrowth [70].…”

Section: Discussionmentioning

confidence: 99%

Enhanced Neuronal Survival and Neurite Outgrowth Triggered by Novel Small Organic Compounds Mimicking the LewisX Glycan

et al. 2018

View full text Add to dashboard Cite

Glycosylation fine-tunes signal transduction of adhesion molecules during neural development and supports synaptic plasticity and repair after injury in the adult nervous system. One abundantly expressed neural glycan is LewisX (LeX). Although it is known that its expression starts at the formation of the neural tube during the second embryonic week in the mouse and peaks during the first postnatal week, its functional relevance is only rudimentarily understood. To gain better insights into the functions of this glycan, we identified small organic compounds that mimic structurally and functionally this glycan glycosidically linked to several neural adhesion molecules. Mimetic compounds were identified by competitive enzyme-linked immunosorbent assay (ELISA) using the LeX-specific monoclonal antibodies L5 and SSEA-1 for screening a library of small organic molecules. In this assay, antibody binding to substrate-coated LeX glycomimetic peptide is measured in the presence of compounds, allowing identification of molecules that inhibit antibody binding and thereby mimic LeX. Gossypol, orlistat, ursolic acid, folic acid, and tosufloxacin inhibited antibody binding in a concentration-dependent manner. With the aim to functionally characterize the molecular consequences of the compounds' actions, we here present evidence that, at nM concentrations, the mimetic compounds enhance neurite outgrowth and promote neuronal survival of cultured mouse cerebellar granule cells via, notably, distinct signal transduction pathways. These findings raise hopes that these LeX mimetics will be powerful tools for further studying the functions of LeX and its effects in acute and chronic nervous system disease models. It is worth mentioning in this context that the LeX compounds investigated in the present study have been clinically approved for different therapies.

show abstract

Section: Discussionmentioning

confidence: 99%

Enhanced Neuronal Survival and Neurite Outgrowth Triggered by Novel Small Organic Compounds Mimicking the LewisX Glycan

et al. 2018

View full text Add to dashboard Cite

show abstract

“…We have recently identified intrathecally synthesized IgA/IgG autoantibodies to the SV-associated protein SynI in several patients suffering from various neuropsychiatric diseases, including limbic encephalitis, multiple sclerosis, depression, anxiety, and bipolar disorders 13,14,23 . SynI is a SV phosphoprotein playing multiple roles in synaptic transmission and plasticity.…”

Section: Discussionmentioning

confidence: 99%

“…To investigate potential pathogenic effects of SynI autoantibodies, we treated primary neurons with the CSF of a limbic encephalitis and clinical isolated syndrome patients (herein referred to as LE-CSF and CIS-CSF, respectively) that were characterized by high titers of IgG and IgA autoantibodies against SynI 13,14 . As control, we pooled CSF from two patients with non-inflammatory neurological disorders that were negative for antineuronal autoantibodies (herein referred to as control CSF).…”

Section: Syni Autoantibodies From Patient Csf Impair Excitatory and Imentioning

confidence: 99%

“…Nonsense and missense mutations in the gene encoding SynI have been associated with epilepsy, autism spectrum disorder (ASD) and intellectual disability in humans [9][10][11][12] . SynI autoantibodies have been identified in serum and CSF from patients suffering of various neurological disorders, including limbic encephalitis, multiple sclerosis, epilepsy, anxiety, depressive and bipolar disorders, but not in healthy controls 13,14 . However, no studies correlating the effect of these antibodies to the brain pathology have been published to date.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Autoantibodies to synapsin I sequestrate synapsin I and alter synaptic function

et al. 2019

Self Cite

View full text Add to dashboard Cite

Synapsin I is a phosphoprotein that coats the cytoplasmic side of synaptic vesicles and regulates their trafficking within nerve terminals. Autoantibodies against Syn I have been described in sera and cerebrospinal fluids of patients with numerous neurological diseases, including limbic encephalitis and clinically isolated syndrome; however, the effects and fate of autoantibodies in neurons are still unexplored. We found that in vitro exposure of primary hippocampal neurons to patient's autoantibodies to SynI decreased the density of excitatory and inhibitory synapses and impaired both glutamatergic and GABAergic synaptic transmission. These effects were reproduced with a purified SynI antibody and completely absent in SynI knockout neurons. Autoantibodies to SynI are internalized by FcγII/III-mediated endocytosis, interact with endogenous SynI, and promote its sequestration and intracellular aggregation. Neurons exposed to human autoantibodies to SynI display a reduced density of SVs, mimicking the SynI loss-of-function phenotype. Our data indicate that autoantibodies to intracellular antigens such as SynI can reach and inactivate their targets and suggest that an antibody-mediated synaptic dysfunction may contribute to the evolution and progression of autoimmune-mediated neurological diseases positive for SynI autoantibodies.

show abstract

“…Although MS remains the most common etiology for inflammatory demyelinating diseases of the central nervous system (CNS), the autoimmune disease neuromyelitis optica spectrum disorder (NMOSD) is a major differential diagnosis. The discovery of autoantibodies, such as aquaporin 4-IgG (AQP4-IgG) followed by myelin oligodendrocyte glycoprotein-IgG (MOG-IgG), and likely more to come [ 1 , 2 ], has further broadened the differential diagnosis of inflammatory demyelinating diseases. This is with the understanding that AQP4-antibody-associated NMOSD is frequently added to primarily inflammatory demyelinating diseases, although it is an astrocytopathy followed by oligodendrocytopathy and demyelination [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

Pattern Recognition of the Multiple Sclerosis Syndrome

2017

View full text Add to dashboard Cite

During recent decades, the autoimmune disease neuromyelitis optica spectrum disorder (NMOSD), once broadly classified under the umbrella of multiple sclerosis (MS), has been extended to include autoimmune inflammatory conditions of the central nervous system (CNS), which are now diagnosable with serum serological tests. These antibody-mediated inflammatory diseases of the CNS share a clinical presentation to MS. A number of practical learning points emerge in this review, which is geared toward the pattern recognition of optic neuritis, transverse myelitis, brainstem/cerebellar and hemispheric tumefactive demyelinating lesion (TDL)-associated MS, aquaporin-4-antibody and myelin oligodendrocyte glycoprotein (MOG)-antibody NMOSD, overlap syndrome, and some yet-to-be-defined/classified demyelinating disease, all unspecifically labeled under MS syndrome. The goal of this review is to increase clinicians’ awareness of the clinical nuances of the autoimmune conditions for MS and NMSOD, and to highlight highly suggestive patterns of clinical, paraclinical or imaging presentations in order to improve differentiation. With overlay in clinical manifestations between MS and NMOSD, magnetic resonance imaging (MRI) of the brain, orbits and spinal cord, serology, and most importantly, high index of suspicion based on pattern recognition, will help lead to the final diagnosis.

show abstract

Synapsin-antibodies in psychiatric and neurological disorders: Prevalence and clinical findings

Cited by 16 publications

References 12 publications

Enhanced Neuronal Survival and Neurite Outgrowth Triggered by Novel Small Organic Compounds Mimicking the LewisX Glycan

Enhanced Neuronal Survival and Neurite Outgrowth Triggered by Novel Small Organic Compounds Mimicking the LewisX Glycan

Autoantibodies to synapsin I sequestrate synapsin I and alter synaptic function

Pattern Recognition of the Multiple Sclerosis Syndrome

Contact Info

Product

Resources

About