Researchers capture images of antibodies attacking neuron receptors using Cryo-Electron Microscopy Facility

Scientists have for the first time photographed an autoantibody coupled to a receptor on the surface of a nerve cell using the Cryo-Electron Microscopy Facility at UT Southwestern, illuminating the physical process underlying a neurological autoimmune illness.

Researchers capture images of antibodies attacking neuron receptors using Cryo-Electron Microscopy Facility
Colleen M. Noviello, PhD. Image Credit: UT Southwestern Medical Center.

The study’s authors suggested that the results, which were published in Cell, might help develop new techniques for identifying and treating autoimmune diseases.

We’re entering a new era of understanding how the autoimmune disease works in the central nervous system.”

Colleen M. Noviello PhD, Assistant Professor, Neuroscience, UT Southwestern Medical Center

Dr Noviello concentrates on gaining cryo-electron microscopy (cryo-EM) images down to an atomic level of resolution.

Dr Noviello co-led the study with Ryan Hibbs PhD, Associate Professor of Neuroscience and Biophysics, an Effie Marie Cain Scholar in Medical Research, and an Investigator in the Peter O’Donnell Jr. Brain Institute and Harald Prüss of Universitätsmedizin Berlin.

Autoimmune disorders, a group of illnesses in which the immune system destroys healthy body tissues, have been the subject of decades of research.

Dr Noviello pointed out that the first autoimmune condition that targeted a neural receptor protein was just identified 15 years ago. Since then, several additional illnesses that fit this description have been discovered, according to researchers.

A good example of this is autoimmune encephalitis, which is marked by the abrupt development of severe symptoms like psychosis, seizures, movement difficulties, reduced consciousness, and issues with the autonomic nerve system, which regulates involuntary bodily activities.

The GABAA receptor is a protein that is found on the surface of synapses, which are specialized structures that connect brain cells. Lately, German researchers examined a patient, who was 8 years old at the time, whose autoimmune encephalitis appeared to be brought on by antibodies that attack the GABAA receptor.

To maintain proper transmission between nerve cells, this receptor balances the electrical impulses produced by excitatory receptors by inhibiting neuronal activation.

Drs Noviello, Hibbs, and their associates in the Hibbs lab used cryo-EM, a method that freezes proteins in place to get high-resolution microscopic pictures, to determine that two types of antibodies produced from this young patient’s immune cells readily attached to the GABAA receptor.

The Cancer Prevention and Research Institute of Texas (CPRIT) helped UTSW open its cryo-EM laboratory in 2016, which offers 3D imaging of biological molecules with atomic resolution.

Images demonstrate that the antibodies protect the GABAA receptor from inhibiting neuronal signaling both collectively and individually. This results in neurons becoming excessively electrically thrilled, which causes brain inflammation, cell death, and seizures that are typical of autoimmune encephalitis.

According to Dr Noviello, screening for these antibodies could improve the diagnosis of this ailment. Likewise, figuring out how to prevent these antibodies from interacting with their targets could improve treatment options.

Dr Hibbs said he, Dr Noviello, and their coworkers intend to make the study of these disorders using cryo-EM a focus of the Hibbs lab’s research in the future because knowledge of autoimmune nervous system diseases is still in its infancy.

To investigate other autoimmune diseases that impact the central nervous system, the team is already working with Nancy Monson PhD, Associate Professor of Neurology and Immunology, and Steven Vernino MD, PhD, Professor of Neurology, Vice Chair for Education and Faculty Affairs, and Distinguished Teaching Professor.

Dr Vernino holds both Dr Bob and Jean Smith Foundation Distinguished Chair in Neuromuscular Disease Research and the Rex Griswold Distinguished Professorship in Multiple System Atrophy.

Jinfeng Teng and other scientists from UTSW also contributed to this investigation.

Source:
Journal reference:

Noviello, C. M., et al. (2022) Structural mechanisms of GABAA receptor autoimmune encephalitis. Cell. doi.org/10.1016/j.cell.2022.06.025.

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