Synapsin I Identified as a Novel Brain-Specific Autoantigen

Gitlits, Veronika M; Sentry, John W.; Matthew, Mary L.S.M.; Smith, Ian; Toh, Ban Hock

doi:10.2310/6650.2001.33973

Cited by 12 publications

(5 citation statements)

References 24 publications

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“… 3 Antibodies to synapsin I were previously identified in serum of a patient with discoid lupus erythematosus, but these antibodies only reacted with denatured synapsin in immunoblots and did not bind to frozen rat brain section or synapsin-transfected cells. 4 In contrast, in addition to the detection of denatured synapsin in immunoblots, our patient's antibodies also recognized conformational synapsin in tissue section and CBAs, strongly suggesting that the previously identified antibodies to synapsin and the anti-synapsin antibodies of our patient target different epitopes. Likewise, the fact that our patient's antibodies detect conformational synapsin indicates a higher likelihood of binding to the target in vivo.…”

Section: Discussionsupporting

confidence: 49%

Intrathecal immunoglobulin A and G antibodies to synapsin in a patient with limbic encephalitis

Piepgras

Höltje

Otto

et al. 2015

Neurol Neuroimmunol Neuroinflamm

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Objective:To report on the identification of intrathecally synthesized immunoglobulin A (IgA) and immunoglobulin G (IgG) antibodies to synapsin, a synaptic vesicle-associated protein, in a patient with limbic encephalitis.Methods:Methods included clinical characterization, indirect immunofluorescence, immunoprecipitation, mass spectrometry, immunoblots of wild-type and synapsin I/II/III knockout mice, and cell-based assays with synapsin Ia, Ib, IIa, and IIb plasmids.Results:A 69-year-old man presented with confusion, disorientation, seizures, and left hippocampal hyperintensities on MRI. CSF examinations revealed an intrathecal IgA and IgG synthesis. Except for IgG antibodies to voltage-gated potassium channels in CSF, screening for known neuronal autoantibodies in serum and CSF was negative. However, indirect immunofluorescence using the patient's CSF showed binding of IgA to mouse hippocampus, amygdala, and cerebellum. Immunoprecipitation with CSF IgA followed by mass spectrometry identified synapsin as autoantigenic target. Knockout tissues and cell-based assays confirmed that IgA and IgG in the patient's CSF and serum reacted with synapsin Ia, Ib, and IIa. Calculation of antibody indices proved intrathecal synthesis of anti-synapsin IgA and IgG. The patient responded clinically to immunotherapy but developed left hippocampal atrophy. CSF IgA or IgG of the patient did not bind to live, unfixed, and nonpermeabilized mouse hippocampal neurons, compatible with synapsin being an intracellular antigen.Conclusions:This report identifies isoforms of the synaptic vesicle-associated protein synapsin as targets of intrathecally produced IgA and IgG antibodies in a patient with limbic encephalitis. Future studies should clarify the prevalence and pathogenic relevance of anti-synapsin antibodies in limbic encephalitis.

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Section: Discussionsupporting

confidence: 49%

Intrathecal immunoglobulin A and G antibodies to synapsin in a patient with limbic encephalitis

Piepgras

Höltje

Otto

et al. 2015

Neurol Neuroimmunol Neuroinflamm

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“…Recently, auto-antibodies to synapsin Ia have been detected in the sera of patients with lupus erythematosus and rheumatoid arthritis, providing a potentially important clue to the molecular basis of neuropsychiatric syndromes that are found in some patients with autoimmune disease (58). The possible relationship between isoAsp formation in brain proteins and autoimmune-related neurological disorders would seem to warrant further study.…”

Section: Discussionmentioning

confidence: 99%

Synapsin I Is a Major Endogenous Substrate for Protein L-Isoaspartyl Methyltransferase in Mammalian Brain

Reissner

Paranandi

Luc

et al. 2006

Journal of Biological Chemistry

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The accumulation of potentially deleterious L-isoaspartyl linkages in proteins is prevented by the action of protein L-isoaspartyl O-methyltransferase, a widely distributed enzyme that is particularly active in mammalian brain. Methyltransferase-deficient (knock-out) mice exhibit greatly increased levels of isoaspartate and typically succumb to fatal epileptic seizures at 4 -10 weeks of age. The link between isoaspartate accumulation and the neurological abnormalities of these mice is poorly understood. Here, we demonstrate that synapsin I from knock-out mice contains 0.9 ؎ 0.3 mol of isoaspartate/mol of synapsin, whereas the levels in wild-type and heterozygous mice are undetectable. Transgenic mice that selectively express methyltransferase only in neurons show reduced levels of synapsin damage, and the degree of reduction correlates with the phenotype of these mice. Isoaspartate levels in synapsin from the knock-out mice are five to seven times greater than those in the average protein from brain cytosol or from a synaptic vesicle-enriched fraction. The isoaspartyl sites in synapsin from knock-out mice are efficiently repaired in vitro by incubation with purified methyltransferase and S-adenosyl-L-methionine. These findings demonstrate that synapsin I is a major substrate for the isoaspartyl methyltransferase in neurons and suggest that isoaspartate-related alterations in the function of presynaptic proteins may contribute to the neurological abnormalities of mice deficient in this enzyme. Fig. 1, dashed arrows) constitutes a major pathway for spontaneous protein damage at physiological pH and temperature (1-3). The internal ␣-carboxyl characteristic of isoaspartyl sites is selectively methylated by a widely distributed protein L-isoaspartyl O-methyltransferase (PIMT) 2 (4 -6). Considerable evidence suggests that PIMT functions to repair this damage in vivo by the mechanism illustrated in Fig. 1 (solid arrows). PIMT selectively methylates the atypical ␣-carboxyl of the isoAsp site. This is followed immediately by a spontaneous demethylation to form a metastable succinimide. Spontaneous hydrolysis of the succinimide over a time course of 2-4 h generates a normal L-aspartyl site with an efficiency of 15-30%. Purified PIMT catalyzes conversion of isoaspartyl sites to normal Asp-Xaa linkages in synthetic peptides (7-9) and has been shown to restore function to isoaspartate-containing forms of proteins such as calmodulin (10) and the Escherichia coli phosphocarrier protein HPr (11). Pharmacological inhibition of PIMT activity in rat PC12 cells leads to reversible accumulation of isoaspartyl sites in a variety of proteins, including tubulin (12) and histone H2B (13). Formation of isoaspartyl sites (Studies with PIMT-deficient mice further support a repair function for PIMT (14,15). Whereas proteins in extracts from wild-type or heterozygous PIMT mice contain only trace levels of isoaspartate, proteins in extracts from knock-out mice show greatly increased isoaspartate levels in extracts from all tissues examined, w...

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“…For example, isoaspartyl peptides have been shown to trigger an autoimmune response [46], and it has been hypothesized that the presence of isoAsp in key proteins may contribute to autoimmune diseases such as lupus erythematosus [43]. In fact, both H2 B and synapsin I have been identified as autoantigens in some forms of this disease [47,48].…”

Section: Evidence That Pimt Mediates Protein Repair In Vitro and In Vivomentioning

confidence: 99%

Deamidation and isoaspartate formation in proteins: unwanted alterations or surreptitious signals?

Reissner

Aswad

2003

Cellular and Molecular Life Sciences (CMLS)

252

270

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Formation of betalinked Asp-Xaa peptide bonds--isoaspartyl (isoAsp) sites--arise in proteins via succinimide-linked deamidation of asparagine or dehydration of aspartate, reactions which represent a major source of spontaneous protein damage under physiological conditions. Accumulation of atypical isoaspartyl sites is minimized in vivo by the activity of protein L-isoaspartyl O-methyltransferase (PIMT), which regenerates a normal peptide bond. Loss of PIMT has harmful consequences, especially in neurons; thus, formation of isoAsp sites and their subsequent correction by PIMT is widely believed to constitute an important pathway of protein damage and repair. Recent evidence is mounting, however, that deamidation and isoaspartate formation may, in some instances, constitute a novel mechanism for intentional modification of protein structure. Herein we describe the mechanism of Asx rearrangement, summarize the evidence that PIMT serves an important repair function, and then focus on emerging evidence that deamidation and isoAsp formation may sometimes have a useful function.

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Synapsin I Identified as a Novel Brain-Specific Autoantigen

Cited by 12 publications

References 24 publications

Intrathecal immunoglobulin A and G antibodies to synapsin in a patient with limbic encephalitis

Intrathecal immunoglobulin A and G antibodies to synapsin in a patient with limbic encephalitis

Synapsin I Is a Major Endogenous Substrate for Protein L-Isoaspartyl Methyltransferase in Mammalian Brain

Deamidation and isoaspartate formation in proteins: unwanted alterations or surreptitious signals?

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