{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T01:52:13Z","timestamp":1760233933721,"version":"build-2065373602"},"reference-count":40,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,22]],"date-time":"2021-02-22T00:00:00Z","timestamp":1613952000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 ES010563","T32 ES007028","T15 LM007450","R01 ES016931"],"award-info":[{"award-number":["R01 ES010563","T32 ES007028","T15 LM007450","R01 ES016931"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Manganese (Mn) is a biologically essential metal, critical as a cofactor for numerous enzymes such a glutamine synthetase and kinases such as ataxia-telangiectasia mutated (ATM). Similar to other essential metals such as iron and zinc, proper levels of Mn need to be achieved while simultaneously being careful to avoid excess levels of Mn that can be neurotoxic. A lifetime of occupational exposure to Mn can often lead to a Parkinsonian condition, also known as \u201cmanganism\u201d, characterized by impaired gait, muscle spasms, and tremors. Despite the importance of its regulation, the mechanisms underlying the transport and homeostasis of Mn are poorly understood. Rather than taking a protein or gene-targeted approach, our lab recently took a high-throughput-screening approach to identify 41 small molecules that could significantly increase or decrease intracellular Mn in a neuronal cell model. Here, we report characterization of these small molecules, which we refer to as the \u201cMn toolbox\u201d. We adapted a Fura-2-based assay for measuring Mn concentration and for measuring relative concentrations of other divalent metals: nickel, copper, cobalt, and zinc. Of these 41 small molecules, we report here the identification of three that selectively influence cellular Mn but do not influence the other divalent metals tested. The patterns of activity across divalent metals and the discovery of Mn-selective small molecules has potential pharmacological and scientific utility.<\/jats:p>","DOI":"10.3390\/molecules26041175","type":"journal-article","created":{"date-parts":[[2021,2,22]],"date-time":"2021-02-22T20:42:51Z","timestamp":1614026571000},"page":"1175","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of Three Small Molecules That Can Selectively Influence Cellular Manganese Levels in a Mouse Striatal Cell Model"],"prefix":"10.3390","volume":"26","author":[{"given":"Kyle J.","family":"Horning","sequence":"first","affiliation":[{"name":"Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xueqi","family":"Tang","sequence":"additional","affiliation":[{"name":"School of Health Sciences, Purdue University, West Lafayette, IN 47906, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Morgan G.","family":"Thomas","sequence":"additional","affiliation":[{"name":"School of Health Sciences, Purdue University, West Lafayette, IN 47906, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2619-1656","authenticated-orcid":false,"given":"Michael","family":"Aschner","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology, Albert Einstein College of Medicine Bronx, New York, NY 10461, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8728-3346","authenticated-orcid":false,"given":"Aaron B.","family":"Bowman","sequence":"additional","affiliation":[{"name":"School of Health Sciences, Purdue University, West Lafayette, IN 47906, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6312","DOI":"10.1074\/jbc.REV119.009453","article-title":"Brain manganese and the balance between essential roles and neurotoxicity","volume":"295","author":"Balachandran","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1093\/toxsci\/kfq387","article-title":"Manganese Uptake and Distribution in the Brain after Methyl Bromide-Induced Lesions in the Olfactory Epithelia","volume":"120","author":"Thompson","year":"2010","journal-title":"Toxicol. Sci."},{"key":"ref_3","first-page":"793","article-title":"Differential deposition of Manganese in the rat brain following subchronic exposure to manganese: A T1-weighted magnetic reso-nance imaging study","volume":"10","author":"Finkelstein","year":"2008","journal-title":"Isr. Med. Assoc. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/s40572-017-0136-1","article-title":"Relationships Between Essential Manganese Biology and Manganese Toxicity in Neurological Disease","volume":"4","author":"Pfalzer","year":"2017","journal-title":"Curr. Environ. Health Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.jtemb.2013.08.005","article-title":"New insights into manganese toxicity and speciation","volume":"28","author":"Michalke","year":"2014","journal-title":"J. Trace Elements Med. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/B978-0-12-410502-7.00013-2","article-title":"Manganese and the Brain","volume":"110","author":"Tuschl","year":"2013","journal-title":"Int. Rev. Neurobiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.neuro.2013.05.003","article-title":"Decreased brain volumes in manganese-exposed welders","volume":"37","author":"Chang","year":"2013","journal-title":"NeuroToxicology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1111\/j.1471-4159.2008.05695.x","article-title":"Impairment of nigrostriatal dopamine neurotransmission by manganese is mediated by pre-synaptic mechanism(s): Implications to manganese-induced parkinsonism","volume":"107","author":"Guilarte","year":"2008","journal-title":"J. Neurochem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1111\/j.1471-4159.2009.06445.x","article-title":"Disease-toxicant screen reveals a neuroprotective interaction between Huntington\u2019s disease and manganese exposure","volume":"112","author":"Williams","year":"2009","journal-title":"J. Neurochem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1596","DOI":"10.1016\/j.bbadis.2017.02.013","article-title":"Reduced bioavailable manganese causes striatal urea cycle pathology in Huntington\u2019s disease mouse model","volume":"1863","author":"Bichell","year":"2017","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1908","DOI":"10.1093\/brain\/awf180","article-title":"Impaired glutamate transport and glutamate-glutamine cycling: Downstream effects of the Huntington mutation","volume":"125","author":"Behrens","year":"2002","journal-title":"Brain"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1016\/0024-3205(82)90090-X","article-title":"Glutamine synthetase activity in Huntington\u2019s disease","volume":"31","author":"Carter","year":"1982","journal-title":"Life Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1007\/s00216-004-2697-8","article-title":"Regional distribution of manganese, iron, copper, and zinc in the rat brain during development","volume":"380","author":"Tarohda","year":"2004","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1016\/j.tiv.2012.07.005","article-title":"Manganese-induced toxicity in normal and human B lymphocyte cell lines containing a homozygous mutation in parkin","volume":"26","author":"Roth","year":"2012","journal-title":"Toxicol. Vitr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.neuro.2005.10.008","article-title":"Acute manganese administration alters dopamine transporter levels in the non-human primate striatum","volume":"27","author":"Chen","year":"2006","journal-title":"NeuroToxicology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1039\/C5MT00052A","article-title":"Loss of pdr-1\/parkin influences Mn homeostasis through altered ferroportin expression in C. elegans","volume":"7","author":"Chakraborty","year":"2015","journal-title":"Metallomics"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/j.neuro.2017.07.030","article-title":"Familial manganese-induced neurotoxicity due to mutations in SLC30A10 or SLC39A14","volume":"64","author":"Mukhopadhyay","year":"2018","journal-title":"NeuroToxicology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.1093\/hmg\/ddr606","article-title":"PARK9-associated ATP13A2 localizes to intracellular acidic vesicles and regulates cation homeostasis and neuronal integrity","volume":"21","author":"Ramonet","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/S0304-3940(01)02341-2","article-title":"Manganese induces endoplasmic reticulum (ER) stress and activates multiple caspases in nigral dopaminergic neuronal cells, SN4741","volume":"316","author":"Chun","year":"2001","journal-title":"Neurosci. Lett."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/j.neuro.2012.01.007","article-title":"ATP13A2 (PARK9) polymorphisms influence the neurotoxic effects of manganese","volume":"33","author":"Rentschler","year":"2012","journal-title":"NeuroToxicology"},{"key":"ref_21","first-page":"239","article-title":"Occupa-tional exposure to manganese, copper, lead, iron, mercury and zinc and the risk of Parkinson\u2019s disease","volume":"20","author":"Gorell","year":"1999","journal-title":"NeuroToxicology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3825","DOI":"10.1093\/hmg\/ddz209","article-title":"Acute manganese treatment restores defective autophagic cargo loading in Huntington\u2019s disease cell lines","volume":"28","author":"Bryan","year":"2019","journal-title":"Hum. Mol. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1007\/s12035-019-01824-1","article-title":"Manganese Acts upon Insulin\/IGF Receptors to Phosphorylate AKT and In-crease Glucose Uptake in Huntington\u2019s Disease Cells","volume":"57","author":"Bryan","year":"2020","journal-title":"Mol. Neurobiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1093\/toxsci\/kfq174","article-title":"Altered Manganese Homeostasis and Manganese Toxicity in a Huntington\u2019s Disease Striatal Cell Model Are Not Explained by Defects in the Iron Transport System","volume":"117","author":"Williams","year":"2010","journal-title":"Toxicol. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1002\/jnr.1256","article-title":"Distribution of Divalent Metal Transporter 1 and Metal Transport Protein 1 in the Normal and Belgrade Rat","volume":"1207","author":"Burdo","year":"2001","journal-title":"J. Neurosci. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"30485","DOI":"10.1074\/jbc.M112.364208","article-title":"Substrate Profile and Metal-ion Selectivity of Human Divalent Metal-ion Transporter-1*","volume":"287","author":"Illing","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1023\/A:1020702213099","article-title":"DMT1: A mammalian transporter for multiple metals","volume":"16","author":"Garrick","year":"2003","journal-title":"BioMetals"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.neuro.2012.10.018","article-title":"Manganese transport via the transferrin mechanism","volume":"34","author":"Gunter","year":"2013","journal-title":"NeuroToxicology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0161-813X(02)00089-X","article-title":"Manganese Distribution Across the Blood\u2013Brain Barrier","volume":"24","author":"Crossgrove","year":"2003","journal-title":"NeuroToxicology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e1042648","DOI":"10.1080\/21624054.2015.1042648","article-title":"SLC30A10: A novel manganese transporter","volume":"4","author":"Chen","year":"2015","journal-title":"Worm"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1111\/cge.13184","article-title":"Hypermanganesemia with dystonia, polycythemia and cirrhosis in 10 patients: Six novel SLC30A10 mutations and further phenotype delineation","volume":"93","author":"Zaki","year":"2018","journal-title":"Clin. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bbrc.2013.01.058","article-title":"Manganese efflux in Parkinsonism: Insights from newly characterized SLC30A10 mutations","volume":"432","author":"DeWitt","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"6801","DOI":"10.1038\/srep06801","article-title":"Cellular manganese content is developmentally regulated in human dopaminergic neurons","volume":"4","author":"Kumar","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"12.18.1","DOI":"10.1002\/0471140856.tx1218s48","article-title":"Cellular fura-2 Manganese Extraction Assay (CFMEA)","volume":"48","author":"Kwakye","year":"2011","journal-title":"Curr. Protoc. Toxicol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1016\/j.neuro.2011.01.002","article-title":"Novel high-throughput assay to assess cellular manganese levels in a striatal cell line model of Huntington\u2019s disease confirms a deficit in manganese accumulation","volume":"32","author":"Kwakye","year":"2011","journal-title":"NeuroToxicology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1002\/jbt.21457","article-title":"Optimization of fluorescence assay of cellular manganese status for high throughput screening","volume":"27","author":"Kumar","year":"2012","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1007\/s12011-018-1531-7","article-title":"Small Molecule Modifiers of In Vitro Manganese Transport Alter Toxicity in vivo","volume":"188","author":"Peres","year":"2018","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1128\/mBio.02555-20","article-title":"A Small-Molecule Modulator of Metal Homeostasis in Gram-Positive Pathogens","volume":"11","author":"Juttukonda","year":"2020","journal-title":"mBio"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1093\/hmg\/ddu609","article-title":"A novel manganese-dependent ATM-p53 signaling pathway is selectively impaired in patient-based neuroprogenitor and murine striatal models of Huntington\u2019s disease","volume":"24","author":"Tidball","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.neuro.2017.07.026","article-title":"Phosphatidylinositol 3 kinase (PI3K) modulates manganese homeostasis and manganese-induced cell signaling in a murine striatal cell line","volume":"64","author":"Bryan","year":"2018","journal-title":"NeuroToxicology"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/4\/1175\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:28:14Z","timestamp":1760160494000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/4\/1175"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,22]]},"references-count":40,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["molecules26041175"],"URL":"https:\/\/doi.org\/10.3390\/molecules26041175","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2021,2,22]]}}}