Project Details
Projekt
Neuropathic pain induced by anti-Caspr2 autoantibodies: pathogenesis and resolution
Subject Area
Molecular and Cellular Neurology and Neuropathology
Term
since 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 426503586
Autoantibodies against proteins of the voltage-gated potassium channel (VGKC) complex, particularly Contactin-associated protein 2 (Caspr2) and Leucine-rich Glioma Inactivated Protein 1 (LGI1), are known to induce autoimmune encephalitis and neuromyotonia. Neuropathic pain was described as a characteristic symptom of patients with Caspr2 and LGI1 autoantibody associated encephalitis. In some patients, neuropathic pain is the only symptom. Here, we aim to elucidate the pathogenic mechanisms inducing pain in Caspr2-associated disease as the pre-condition for the development of effective treatment for pain resolution. We hypothesize that Caspr2 expressed in the sensory nervous system is a mediator of neuronal sensitization, thus inducing pain perception. In the clinical part of the project, we will study the prevalence of anti-Caspr2 in patients with isolated neuropathic pain and aim at characterizing neuropathic pain in a large cohort of anti-Caspr2-positive patients (WP 1). The molecular part of our project will use dorsal root ganglia (DRG) neurons as a possible site of pathogenicity of neuropathic pain in patients with Caspr2 autoantibodies. By passive transfer of IgG of anti-Caspr2-positive patients to rats, we will examine pain induction and resolution in vivo and will investigate the effects of anti-Caspr2 on protein expression as well as inflammatory responses (WP 2). Next, we will examine short-term and long-term effects of Caspr2 autoantibodies with consequences on the expression and assembly of the VGKC complex (WP 3). Alterations at the protein expression level upon autoantibody binding will be investigated but also protein expression after a resolution period in the absence of Caspr2 autoantibodies will be analyzed. Moreover, to determine altered organization of the VGKC, high resolution microscopy techniques will be used, e.g SIM microscopy and dSTORM. Changes in the organization of the VGKC complex might impair the function of potassium channels and thus lead to hyperexcitability of nociceptive neurons. The functional analysis of the associated potassium channels will be evaluated in vitro using patch clamp techniques and correlated to the obtained changes in protein expression (WP 4). With these data, we expect to understand the molecular mechanism of neuronal sensitization upon Caspr2 autoantibody binding. Our analysis aims to comprehend pain resolution mechanisms in this type of neuropathic pain and the natural disease progression, a prerequisite to develop novel therapeutic options.
DFG Programme
Clinical Research Units
