Danish and British dementia ITM2b/BRI2 mutations reduce BRI2 protein stability and impair glutamatergic synaptic transmission
| Autor: | Alexander Lemenze, Wen Yao, Luciano D'Adamio, Tao Yin |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male KI knock-in ERLAD ER-to-lysosomes-associated degradation Denmark Biochemistry Hippocampus Synaptic Transmission PPF paired-pulse facilitation Mice neurodegenerative disease FBD familial British dementia LTP long-term potentiation Glutamates EMEM Eagle's Minimum Essential Medium Cells Cultured education.field_of_study Protein Stability Neurodegeneration Glutamate receptor Long-term potentiation Female PPR paired-pulse ratio Research Article Neural facilitation glutamate Mice Transgenic Biology Neurotransmission mEPSC miniature excitatory postsynaptic currents 03 medical and health sciences Glutamatergic medicine Integral membrane protein 2B Animals Humans education Molecular Biology mouse Adaptor Proteins Signal Transducing synaptic plasticity 030102 biochemistry & molecular biology animal model protein turnover Cell Biology medicine.disease United Kingdom Disease Models Animal 030104 developmental biology Synaptic plasticity Mutation Dementia ISI interstimulus interval Neuroscience FDD familial Danish dementia |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X 0021-9258 |
| Popis: | Mutations in integral membrane protein 2B (ITM2b/BRI2) gene cause familial British and Danish dementia (FBD and FDD), autosomal dominant disorders characterized by progressive cognitive deterioration. Two pathogenic mechanisms, which may not be mutually exclusive, have been proposed for FDD and FBD: 1) loss of BRI2 function; 2) accumulation of amyloidogenic mutant BRI2-derived peptides, but the mechanistic details remain unclear. We have previously reported a physiological role of BRI2 in excitatory synaptic transmission at both presynaptic termini and postsynaptic termini. To test whether pathogenic ITM2b mutations affect these physiological BRI2 functions, we analyzed glutamatergic transmission in FDD and FBD knock-in mice, which carry pathogenic FDD and FBD mutations into the mouse endogenous Itm2b gene. We show that in both mutant lines, spontaneous glutamate release and AMPAR-mediated responses are decreased, while short-term synaptic facilitation is increased, effects similar to those observed in Itm2bKO mice. In vivo and in vitro studies show that both pathogenic mutations alter maturation of BRI2 resulting in reduced levels of functional mature BRI2 protein at synapses. Collectively, the data show that FDD and FBD mutations cause a reduction of BRI2 levels and function at synapses, which results in reduced glutamatergic transmission. Notably, other genes mutated in Familial dementia, such as APP, PSEN1/PSEN2, are implicated in glutamatergic synaptic transmission, a function that is altered by pathogenic mutations. Thus, defects in excitatory neurotransmitter release may represent a general and convergent mechanism leading to neurodegeneration. Targeting these dysfunction may offer a unique disease modifying method of therapeutic intervention in neurodegenerative disorders. |
| Databáze: | OpenAIRE |
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