Project Details
Projekt
LGI1 antibody induced pathophysiology at axon initial segments and presynaptic nerve terminals
Subject Area
Molecular and Cellular Neurology and Neuropathology
Molecular Biology and Physiology of Neurons and Glial Cells
Molecular Biology and Physiology of Neurons and Glial Cells
Term
since 2019
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 415914819
Limbic encephalitis with autoantibodies against the protein “leucine-rich glioma inactivated 1” (LGI1) is the second most common subtype of autoimmune encephalitis. The function of LGI1 remains poorly understood but there is evidence that LGI1 is secreted by neurons, forms trans- synaptic dimers, and controls the function of the axon initial segment (AIS). In the first funding period, we found that pathogenic LGI1 antibodies cause an increase in cellular excitability and synaptic release probability. The latter is caused by a reduction in the density of the presynaptic potassium channels Kv1.1 and Kv1.2, which causes broadening of presynaptic action potential. To uncover the underlying mechanisms, we will study the composition and function of the LGI1 protein complex at the AIS and the role of the LGI1 protein complex for the establishment of trans- synaptic nano-columns. To this end, we will combine freeze-fracture replica labeling (R. Shigemoto), super-resolution and expansion microscopy (M. Sauer), and patch-clamp recordings from the AIS (S. Hallermann) as well as the molecular biology of LGI1 in collaboration with the Mercator fellow Prof. Masaki Fukata (Okazaki, Japan), who is a renowned expert on the molecular composition of the LGI1 protein complex. These results will improve our understanding of the multiple roles of the LGI1 protein and will elucidate autoantibody-induced pathomechanisms.
DFG Programme
Research Units
International Connection
Austria
Partner Organisation
Fonds zur Förderung der wissenschaftlichen Forschung (FWF)
Cooperation Partner
Professor Dr. Ryuichi Shigemoto
