title: Activation of a synapse weakening pathway by human Val66 but not Met66 pro-brain-derived neurotrophic factor (proBDNF).
abstract: This study describes a fundamental functional difference between the two main polymorphisms of the pro-form of brain-derived neurotrophic factor (proBDNF), providing an explanation as to why these forms have such different age-related neurological outcomes. Healthy young carriers of the Met66 form (present in ∼30% Caucasians) have reduced hippocampal volume and impaired hippocampal-dependent memory function, yet the same polymorphic population shows enhanced cognitive recovery after traumatic brain injury, delayed cognitive dysfunction during aging, and lower risk of late-onset Alzheimer's disease (AD) compared to those with the more common Val66 polymorphism. To examine the differences between the protein polymorphisms in structure, kinetics of binding to proBDNF receptors and in vitro function, we generated purified cleavage-resistant human variants. Intriguingly, we found no statistical differences in those characteristics. As anticipated, exogenous application of proBDNF Val66 to rat hippocampal slices dysregulated synaptic plasticity, inhibiting long-term potentiation (LTP) and facilitating long-term depression (LTD). We subsequently observed that this occurred via the glycogen synthase kinase 3β (GSK3β) activation pathway. However, surprisingly, we found that Met66 had no such effects on either LTP or LTD. These novel findings suggest that, unlike Val66, the Met66 variant does not facilitate synapse weakening signaling, perhaps accounting for its protective effects with aging.
authors.affiliation: Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, School of Clinical Sciences, Faculty of Health Sciences, University of Bristol, Whitson Street, Bristol BS1 3NY, UK; Learning & Research, School of Clinical Sciences, Faculty of Health Sciences, Southmead Hospital, Bristol BS10 5NB, UK.
authors.forename: Sumangali
authors.initials: S
authors.lastname: Kailainathan
authors.affiliation: Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, School of Clinical Sciences, Faculty of Health Sciences, University of Bristol, Whitson Street, Bristol BS1 3NY, UK; Centre for Synaptic Plasticity, University of Bristol, Whitson Street, Bristol BS1 3NY, UK; Chonnam-Bristol Frontier Laboratory, Biomedical Research Institute, Chonnam National University Hospital, Gwangju 501-757, South Korea.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Piers
authors.affiliation: Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, School of Clinical Sciences, Faculty of Health Sciences, University of Bristol, Whitson Street, Bristol BS1 3NY, UK; Centre for Synaptic Plasticity, University of Bristol, Whitson Street, Bristol BS1 3NY, UK.
authors.forename: Jee Hyun
authors.initials: JH
authors.lastname: Yi
authors.affiliation: Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, School of Clinical Sciences, Faculty of Health Sciences, University of Bristol, Whitson Street, Bristol BS1 3NY, UK; Centre for Synaptic Plasticity, University of Bristol, Whitson Street, Bristol BS1 3NY, UK; Chonnam-Bristol Frontier Laboratory, Biomedical Research Institute, Chonnam National University Hospital, Gwangju 501-757, South Korea.
authors.forename: Seongmin
authors.initials: S
authors.lastname: Choi
authors.affiliation: Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, School of Clinical Sciences, Faculty of Health Sciences, University of Bristol, Whitson Street, Bristol BS1 3NY, UK.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Fahey
authors.affiliation: Medical and Biological Sciences Building, University of St. Andrews, Fife KY16 9TF, UK.
authors.forename: Eva
authors.initials: E
authors.lastname: Borger
authors.affiliation: Medical and Biological Sciences Building, University of St. Andrews, Fife KY16 9TF, UK.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gunn-Moore
authors.affiliation: Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, School of Clinical Sciences, Faculty of Health Sciences, University of Bristol, Whitson Street, Bristol BS1 3NY, UK; Centre for Synaptic Plasticity, University of Bristol, Whitson Street, Bristol BS1 3NY, UK.
authors.forename: Laurie
authors.initials: L
authors.lastname: O'Neill
authors.affiliation: Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, School of Clinical Sciences, Faculty of Health Sciences, University of Bristol, Whitson Street, Bristol BS1 3NY, UK; Centre for Synaptic Plasticity, University of Bristol, Whitson Street, Bristol BS1 3NY, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Lever
authors.affiliation: Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, School of Clinical Sciences, Faculty of Health Sciences, University of Bristol, Whitson Street, Bristol BS1 3NY, UK; Centre for Synaptic Plasticity, University of Bristol, Whitson Street, Bristol BS1 3NY, UK; Chonnam-Bristol Frontier Laboratory, Biomedical Research Institute, Chonnam National University Hospital, Gwangju 501-757, South Korea.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Whitcomb
authors.affiliation: Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, School of Clinical Sciences, Faculty of Health Sciences, University of Bristol, Whitson Street, Bristol BS1 3NY, UK; Centre for Synaptic Plasticity, University of Bristol, Whitson Street, Bristol BS1 3NY, UK; Chonnam-Bristol Frontier Laboratory, Biomedical Research Institute, Chonnam National University Hospital, Gwangju 501-757, South Korea. Electronic address: Kei.Cho@bristol.ac.uk.
authors.forename: Kwangwook
authors.initials: K
authors.lastname: Cho
authors.affiliation: Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, School of Clinical Sciences, Faculty of Health Sciences, University of Bristol, Whitson Street, Bristol BS1 3NY, UK; Learning & Research, School of Clinical Sciences, Faculty of Health Sciences, Southmead Hospital, Bristol BS10 5NB, UK. Electronic address: shelley.allen@bristol.ac.uk.
authors.forename: Shelley J
authors.initials: SJ
authors.lastname: Allen
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D011110:Polymorphism, Genetic; D011498:Protein Precursors / Q000235:genetics* / Q000378:metabolism; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D011498:Protein Precursors; D011994:Recombinant Proteins; C426674:brain-derived neurotrophic factor precursor; D016875:tau Proteins; D007770:L-Lactate Dehydrogenase; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta
keywords: Binding kinetics; Chemical compounds studied in this article; GSK3β inhibitor CT-99021 6-[2-[[4-(2,4-dichlorophenyl)-5-(5-methyl-1H-imidazol-2-yl) pyrimidin-2-yl]] amino] ethylamino] pyridine-3-carbonitrile. Cas no. 252917-06-9; Long-term depression (LTD); Neurotrophin receptors; Pro-brain-derived neurotrophic factor (proBDNF); Val66Met polymorphism