Pathomechanisms in GAD65 autoantibody-associated neurological syndromes

• Applicants: Privatdozentin Dr. Julika Pitsch; Privatdozentin Dr. Franziska Thaler
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases ; Clinical Immunology and Allergology ; Molecular and Cellular Neurology and Neuropathology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 580824647

Glutamic acid decarboxylase 65 (GAD65) is critical for the rapid synthesis of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the central nervous system (CNS). Autoantibodies targeting GAD65 (GAD65 Abs) are typically detected in type 1 diabetes (T1D) and are also associated with certain neurological syndromes, including cerebellar ataxia, stiff-person syndrome, or pharmacoresistant temporal lobe epilepsy (TLE), sometimes preceded by limbic encephalitis (LE). The symptoms may also overlap. While the pathogenic role of GAD65 Abs remains controversial due to the intracellular localisation of GAD65, some studies suggest that they impair GABAergic neurotransmission by inhibiting GAD65 enzymatic function. Neuropathological analyses of brain tissue from patients with GAD65 Ab-positive encephalitis suggest a progressive immune response, including CD8+ T cell infiltration, plasma cell activity, and neuronal degeneration in the early stages of the pathology, followed by atrophy and persistent neurological deficits. Elucidation of the disease mechanisms underlying the neurological syndromes associated with GAD65 Abs is crucial for development of targeted therapies for the severely affected patients. This study aims to elucidate whether monoclonal GAD65 Abs or coexisting non-GAD65 Abs contribute causally to encephalitis, rather than acting as mere passive biomarkers. Understanding their role is essential due to the clinically heterogeneous pattern, the contradictory results of previous studies, and the largely unknown effects of these Abs on neuronal plasticity. Therefore, this study will investigate how patient-derived Abs from GAD65-positive patients with different neurological presentations affect neuronal function using cultured neurons to assess cellular uptake, enzyme activity, neurotransmitter release and changes in neuronal plasticity. The causal role of GAD65 Abs in neuroinflammation in the different neurological phenotypes will be investigated in vivo using a novel experimental mouse model to induce GAD65 Ab production in the CNS and to study neuronal GAD65 Ab uptake and effects on immune activation. The underlying immune mechanisms will be further elucidated by identifying GAD65 reactive B lymphocytes, analysing their transcriptional profiles, receptor characteristics, and migration pathways into the CNS. By applying patient-derived monoclonal Abs, studying their effects on neuronal function and immune activation using various sophisticated models, and investigating the role of GAD65-reactive B lymphocytes in the development and clinical course of GAD65 encephalitis, this project will provide new insights into the pathogenesis of GAD65 Ab-associated neurological syndromes. These findings might promote the identification of novel therapeutic targets in GAD65 Ab-associated neurological diseases.

• DFG Programme: Research Grants