The intracellular domain of major histocompatibility class-I proteins is essential for maintaining excitatory spine density and synaptic ultrastructure in the brain

Major histocompatibility complex class I (MHC-I) proteins are expressed in neurons, where they regulate synaptic plasticity. However, the mechanisms by which MHC-I functions in the CNS remains unknown. Here we describe the first structural analysis of a MHC-I protein, to resolve underlying mechanism...

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Bibliographic Details
Published in:Scientific reports 2023-04, Vol.13 (1), p.6448-6448, Article 6448
Main Authors: Lazarczyk, Maciej J., Eyford, Brett A., Varghese, Merina, Arora, Hitesh, Munro, Lonna, Warda, Tahia, Pfeifer, Cheryl G., Sowa, Allison, Dickstein, Daniel R., Rumbell, Timothy, Jefferies, Wilfred A., Dickstein, Dara L.
Format: Article
Language:English
Subjects:
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Animals
Brain - metabolism
Brain research
Dendritic cells
Endocytosis
Health sciences
Hippocampus - metabolism
Histocompatibility Antigens Class I - genetics
Histocompatibility Antigens Class I - metabolism
Humanities and Social Sciences
Major histocompatibility complex
Morphology
multidisciplinary
Mutation
Nervous system
Neuronal Plasticity - physiology
Neurons
Neurons - metabolism
Peptides
Plasticity
Proteins
Science
Science (multidisciplinary)
Signal Transduction
Spine
Structural analysis
Synaptic density
Synaptic plasticity
Ultrastructure
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Summary:Major histocompatibility complex class I (MHC-I) proteins are expressed in neurons, where they regulate synaptic plasticity. However, the mechanisms by which MHC-I functions in the CNS remains unknown. Here we describe the first structural analysis of a MHC-I protein, to resolve underlying mechanisms that explains its function in the brain. We demonstrate that Y321F mutation of the conserved cytoplasmic tyrosine-based endocytosis motif YXXΦ in MHC-I affects spine density and synaptic structure without affecting neuronal complexity in the hippocampus, a region of the brain intimately involved in learning and memory. Furthermore, the impact of the Y321F substitution phenocopies MHC-I knock-out (null) animals, demonstrating that reverse, outside-in signalling events sensing the external environment is the major mechanism that conveys this information to the neuron and this has a previously undescribed yet essential role in the regulation of synaptic plasticity.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-023-30054-8