title: Cellular manganese content is developmentally regulated in human dopaminergic neurons.
abstract: Manganese (Mn) is both an essential biological cofactor and neurotoxicant. Disruption of Mn biology in the basal ganglia has been implicated in the pathogenesis of neurodegenerative disorders, such as parkinsonism and Huntington's disease. Handling of other essential metals (e.g. iron and zinc) occurs via complex intracellular signaling networks that link metal detection and transport systems. However, beyond several non-selective transporters, little is known about the intracellular processes regulating neuronal Mn homeostasis. We hypothesized that small molecules that modulate intracellular Mn could provide insight into cell-level Mn regulatory mechanisms. We performed a high throughput screen of 40,167 small molecules for modifiers of cellular Mn content in a mouse striatal neuron cell line. Following stringent validation assays and chemical informatics, we obtained a chemical 'toolbox' of 41 small molecules with diverse structure-activity relationships that can alter intracellular Mn levels under biologically relevant Mn exposures. We utilized this toolbox to test for differential regulation of Mn handling in human floor-plate lineage dopaminergic neurons, a lineage especially vulnerable to environmental Mn exposure. We report differential Mn accumulation between developmental stages and stage-specific differences in the Mn-altering activity of individual small molecules. This work demonstrates cell-level regulation of Mn content across neuronal differentiation.
authors.affiliation: 1] Department of Neurology, Vanderbilt University Medical Center, Nashville, TN [2] Medical Scientist Training Program, Vanderbilt University Medical Center, Nashville, TN [3] Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Kumar
authors.affiliation: Department of Chemistry, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Edward W
authors.initials: EW
authors.lastname: Lowe
authors.affiliation: Department of Neurology, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Asad A
authors.initials: AA
authors.lastname: Aboud
authors.affiliation: Department of Neurology, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: M Diana
authors.initials: MD
authors.lastname: Neely
authors.affiliation: Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Rey
authors.initials: R
authors.lastname: Redha
authors.affiliation: 1] Department of Biochemistry, Vanderbilt University Medical Center, Nashville, TN [2] Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Bauer
authors.affiliation: Department of Neurology, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Mihir
authors.initials: M
authors.lastname: Odak
authors.affiliation: 1] Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN [2] Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: C David
authors.initials: CD
authors.lastname: Weaver
authors.affiliation: 1] Department of Chemistry, Vanderbilt University Medical Center, Nashville, TN [2] Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Jens
authors.initials: J
authors.lastname: Meiler
authors.affiliation: Departments of Molecular Pharmacology, Neuroscience, and Pediatrics, Albert Einstein College of Medicine, Bronx NY.
authors.forename: Michael
authors.initials: M
authors.lastname: Aschner
authors.affiliation: 1] Department of Neurology, Vanderbilt University Medical Center, Nashville, TN [2] Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Bowman
mesh_terms: D000818:Animals; D001692:Biological Transport; D059290:Dopaminergic Neurons / Q000737:chemistry / Q000378:metabolism*; D004781:Environmental Exposure; D006706:Homeostasis; D006801:Humans; D007477:Ions / Q000737:chemistry / Q000378:metabolism*; D008345:Manganese / Q000378:metabolism* / Q000633:toxicity; D051379:Mice; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: D007477:Ions; D008345:Manganese