ArticleJournal of neuroinflammation2025
Coexistence of CN1A autoantibodies in GAD65 encephalitis exacerbates neurodegeneration : Novel autoantibodies in GAD65 encephalitis.
Article in Journal of neuroinflammation, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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4 citing papers in PubMed.
- Forkhead box versus NF-κB hippocampal snRNA-seq profiles distinguish anti-Drebrin- and anti-GAD65-positive encephalitis.Journal of neuroinflammation · 2026Article
- Article
- Case report: Thymoma-associated GAD65 autoimmunity: a unifying mechanism for multi-organ injury involving nervous, endocrine, and renal systems.Frontiers in immunology · 2026Article
- Temporal trends indicate an epidemiological shift in the pathology of mesial temporal lobe epilepsy.Journal of neurology · 2025Article
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12 authors.
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Abstract
backgroundAutoantibodies targeting the intracellular 65-kDa isoform of glutamic acid decarboxylase (anti-GAD65) have been associated with a variety of autoimmune-related syndromes involving a spectrum of difficult-to-treat neurological disorders. However, the pathophysiological role of anti-GAD65 in neuroinflammation remains vague. Its understanding may be complicated by the possible pathogenic interaction between anti-GAD65 and potentially coexisting autoantibodies.
methodsWe combined a broad spectrum of approaches ranging from antibody-antigen identification, immunoblotting, immunoprecipitation, mass-spectrometry, cell-based assays, subcellular binding pattern analysis in primary neuronal cultures, and immunohistochemistry to in vitro assays of neuronal uptake, viability, and multi-electrode arrays.
resultsIn anti-GAD65-positive neurological patients, mass-spectrometric analysis revealed cytosolic 5'-nucleotidase 1 A (CN1A syn. NT5C1A) as the most abundant antigen. Subsequent screening of 118 anti-GAD65-positive patients revealed that 32 of them had additional autoantibodies targeting CN1A, which were also present in all available corresponding CSF samples. Limbic encephalitis was more often diagnosed in anti-CN1A/anti-GAD65-positive compared to the anti-GAD65-positive patients. Functionally, incubation of primary hippocampal neurons with anti-GAD65, but not with anti-CN1A, resulted in uptake into GABAergic neurons, neuronal cell death, and increased neuronal network activity. Moreover, simultaneous incubation with both antibodies (anti-CN1A/anti-GAD65) resulted in concomitant intraneuronal uptake in a concentration-dependent manner, which correlated with enhanced autophagy followed by massive neuronal death.
conclusionGAD65 antibodies directly affect neuronal viability and network activity. Co-existing autoantibodies against CN1A, present in anti-GAD65-positive patients, enhance autophagy and subsequent neuronal death in vitro. Clinically, anti-GAD65-positive patients should be screened for anti-CN1A-associated diseases, and evaluation of anti-CN1A in anti-GAD65-related autoimmune conditions may clarify links between systemic autoimmunity and epilepsy.
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