University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
Integrative Physiology and Neuroscience, College of Veterinary Medicine, Washington State University, Pullman, Washington, USA.
Sci Rep. 2020 Jun 3;10(1):9028. doi: 10.1038/s41598-020-65531-x.
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.
脑源性神经营养因子（BDNF）通过其高亲和力受体原肌球蛋白受体激酶-B（TrkB）传递信号，调节神经元发育、突触形成和可塑性。在啮齿动物中，BDNF 和 TrkB 的基因缺失会导致体重增加和一系列神经行为表型。在这里，我们对在一大群患有严重儿童期肥胖症的人群中发现的 BDNF 中的一个新的错义变异和 TrkB 中的七个罕见变异进行了功能表征。在细胞中，E183K BDNF 变异导致成熟肽的加工和分泌受损。TrkB 激酶结构域中的多个变异和细胞外结构域中的一个变异通过多种信号通路导致功能丧失，损害神经突生长，并在海马神经元中显性抑制谷氨酸能突触发生。BDNF/TrkB 变异携带者表现出学习困难、记忆障碍、多动、刻板，有时还表现出适应不良的行为。总之，人类丧失功能的 BDNF/TrkB 变异会损害海马突触发生，可能导致一系列神经行为障碍。
