title: BDNF and Huntingtin protein modifications by manganese: implications for striatal medium spiny neuron pathology in manganese neurotoxicity.
abstract: High levels of manganese (Mn) exposure decrease striatal medium spiny neuron (MSN) dendritic length and spine density, but the mechanism(s) are not known. The Huntingtin (HTT) gene has been functionally linked to cortical brain-derived neurotrophic factor (BDNF) support of striatal MSNs via phosphorylation at serine 421. In Huntington's disease, pathogenic CAG repeat expansions of HTT decrease synthesis and disrupt transport of cortical-striatal BDNF, which may contribute to disease, and Mn is a putative environmental modifier of Huntington's disease pathology. Thus, we tested the hypothesis that changes in MSN dendritic morphology Mn due to exposure are associated with decreased BDNF levels and alterations in Htt protein. We report that BDNF levels are decreased in the striatum of Mn-exposed non-human primates and in the cerebral cortex and striatum of mice exposed to Mn. Furthermore, proBDNF and mature BDNF concentrations in primary cortical and hippocampal neuron cultures were decreased by exposure to Mn confirming the in vivo findings. Mn exposure decreased serine 421 phosphorylation of Htt in cortical and hippocampal neurons and increased total Htt levels. These data strongly support the hypothesis that Mn-exposure-related MSN pathology is associated with decreased BDNF trophic support via alterations in Htt.
authors.affiliation: Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York, USA.
authors.forename: Kirstie H
authors.initials: KH
authors.lastname: Stansfield
authors.forename: Terry Jo
authors.initials: TJ
authors.lastname: Bichell
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Bowman
authors.forename: Tomás R
authors.initials: TR
authors.lastname: Guilarte
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003342:Corpus Striatum / Q000473:pathology*; D049229:Dendritic Spines / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000187:drug effects; D000071058:Huntingtin Protein; D008345:Manganese / Q000494:pharmacology; D020149:Manganese Poisoning / Q000473:pathology*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000648:ultrastructure*; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D008345:Manganese
keywords: BDNF; Huntingtin; cortical; manganese; medium spiny neuron
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