Human BDNF/TrkB variants impair hippocampal synaptogenesis and associate with neurobehavioural abnormalities.

Autor:	Sonoyama T; University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK., Stadler LKJ; University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK., Zhu M; Integrative Physiology and Neuroscience, College of Veterinary Medicine, Washington State University, Pullman, Washington, USA., Keogh JM; University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK., Henning E; University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK., Hisama F; Department of Medicine (Medical Genetics), University of Washington School of Medicine, Seattle, Washington, USA., Kirwan P; University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK., Jura M; University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK., Blaszczyk BK; Department of Biochemistry, 80 Tennis Court Road, CB2 1QW, University of Cambridge, Cambridge, UK., DeWitt DC; Integrative Physiology and Neuroscience, College of Veterinary Medicine, Washington State University, Pullman, Washington, USA., Brouwers B; University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK., Hyvönen M; Department of Biochemistry, 80 Tennis Court Road, CB2 1QW, University of Cambridge, Cambridge, UK., Barroso I; MRC Epidemiology Unit, Addenbrooke's Hospital, Cambridge, UK.; Wellcome Sanger Institute, Cambridge, UK., Merkle FT; University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK., Appleyard SM; Integrative Physiology and Neuroscience, College of Veterinary Medicine, Washington State University, Pullman, Washington, USA., Wayman GA; Integrative Physiology and Neuroscience, College of Veterinary Medicine, Washington State University, Pullman, Washington, USA. waymang@wsu.edu., Farooqi IS; University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK. isf20@cam.ac.uk.
Jazyk:	angličtina
Zdroj:	Scientific reports [Sci Rep] 2020 Jun 03; Vol. 10 (1), pp. 9028. Date of Electronic Publication: 2020 Jun 03.
DOI:	10.1038/s41598-020-65531-x
Abstrakt:	Brain-derived neurotrophic factor (BDNF) signals through its high affinity receptor Tropomyosin receptor kinase-B (TrkB) to regulate neuronal development, synapse formation and plasticity. In rodents, genetic disruption of Bdnf and TrkB leads to weight gain and a spectrum of neurobehavioural phenotypes. Here, we functionally characterised a de novo missense variant in BDNF and seven rare variants in TrkB identified in a large cohort of people with severe, childhood-onset obesity. In cells, the E183K BDNF variant resulted in impaired processing and secretion of the mature peptide. Multiple variants in the kinase domain and one variant in the extracellular domain of TrkB led to a loss of function through multiple signalling pathways, impaired neurite outgrowth and dominantly inhibited glutamatergic synaptogenesis in hippocampal neurons. BDNF/TrkB variant carriers exhibited learning difficulties, impaired memory, hyperactivity, stereotyped and sometimes, maladaptive behaviours. In conclusion, human loss of function BDNF/TrkB variants that impair hippocampal synaptogenesis may contribute to a spectrum of neurobehavioural disorders.
Databáze:	MEDLINE
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