Abstract
Mitochondrial impairment and metal dyshomeostasis are suggested to be associated with many neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and Friedreich's ataxia. Treatments aimed at restoring metal homeostasis are highly effective in models of these diseases, and clinical trials hold promise. However, in general, the effect of these treatments on mitochondrial metal homeostasis is unclear, and the contribution of mitochondrial metal dyshomeostasis to disease pathogenesis requires further investigation. This review describes the role of metals in mitochondria in health, how mitochondrial metals are disrupted in neurodegenerative diseases, and potential therapeutics aimed at restoring mitochondrial metal homeostasis and function.
Papers of special note have been highlighted as: • of interest
References
- 1 . Iron trafficking inside the brain. J. Neurochem. 103(5), 1730–1740 (2007).
- 2 . Copper transport to the brain by the blood–brain barrier and blood–CSF barrier. Brain Res. 1248, 14–21 (2009).
- 3 . Zinc: an underappreciated modulatory factor of brain function. Biochem. Pharmacol. 91(4), 426–435 (2014).
- 4 . A delicate balance: iron metabolism and diseases of the brain. Front. Aging Neurosci. 5, 34 (2013).
- 5 . Metabolism and functions of copper in brain. Prog. Neurobiol. 116, 33–57 (2014).
- 6 . Ion transport and energy metabolism. In: Handbook of Neurochemistry and Molecular Neurobiology. Lajtha A (Ed.). Springer Science+Business Media, NY, USA, 429–463 (2007).
- 7 . Metalloproteins and metal sensing. Nature 460(7257), 823–830 (2009).
- 8 . The mitochondrial proteome and human disease. Annu. Rev. Genomics Hum. Genet. 11, 25–44 (2010).
- 9 . Mitochondrial iron-sulfur protein biogenesis and human disease. Biochimie 100, 61–77 (2014).
- 10 Discovery of genes essential for heme biosynthesis through large-scale gene expression analysis. Cell Metab. 10(2), 119–130 (2009).
- 11 . Mitochondrial respiratory chain complexes as sources and targets of thiol-based redox-regulation. Biochim. Biophys. Acta 1844(8), 1344–1354 (2014).
- 12 . Iron and copper in mitochondrial diseases. Cell Metab. 17(3), 319–328 (2013).
- 13 Evidence for mitochondrial localization of divalent metal transporter 1 (DMT1). FASEB J. (2014).
- 14 . Mitochondrial transporters of the SLC25 family and associated diseases: a review. J. Inherit. Metab. Dis. 37(4), 565–575 (2014).
- 15 . Regulation of mitochondrial iron import through differential turnover of mitoferrin 1 and mitoferrin 2. Mol. Cell Biol. 29(4), 1007–1016 (2009).
- 16 Mitoferrin is essential for erythroid iron assimilation. Nature 440(7080), 96–100 (2006).
- 17 . Deletion of the mitochondrial carrier genes MRS3 and MRS4 suppresses mitochondrial iron accumulation in a yeast frataxin-deficient strain. J. Biol. Chem. 277(27), 24475–24483 (2002).
- 18 . Characterization of two homologous yeast genes that encode mitochondrial iron transporters. J. Biol. Chem. 272(45), 28485–28493 (1997).
- 19 The mitochondrial carrier Rim2 co-imports pyrimidine nucleotides and iron. Biochem. J. 455(1), 57–65 (2013).
- 20 . The yeast mitochondrial carrier proteins Mrs3p/Mrs4p mediate iron transport across the inner mitochondrial membrane. Biochim. Biophys. Acta 1788(5), 1044–1050 (2009).
- 21 . Copper import into the mitochondrial matrix in Saccharomyces cerevisiae is mediated by Pic2, a mitochondrial carrier family protein. J. Biol. Chem. 288(33), 23884–23892 (2013).
- 22 . Activation of superoxide dismutases: putting the metal to the pedal. Biochim. Biophys. Acta 1763(7), 747–758 (2006).
- 23 . Autophagosome dynamics in neurodegeneration at a glance. J. Cell Sci. 128(7), 1259–1267 (2015).
- 24 . Toxic metals and autophagy. Chem. Res. Toxicol. 27(11), 1887–1900 (2014).
- 25 . Iron metabolism and autophagy: a poorly explored relationship that has important consequences for health and disease. Nagoya J. Med. Sci. 77(1–2), 1–6 (2015).
- 26 . ATP13A2 and alpha-synuclein: a metal taste in autophagy. Exp. Neurobiol. 23(4), 314–323 (2014).
- 27 . Biology of ferritin in mammals: an update on iron storage, oxidative damage and neurodegeneration. Arch. Toxicol. 88(10), 1787–1802 (2014).
- 28 A human mitochondrial ferritin encoded by an intronless gene. J. Biol. Chem. 276(27), 24437–24440 (2001).
- 29 . Overexpression of mitochondrial ferritin causes cytosolic iron depletion and changes cellular iron homeostasis. Blood 105(5), 2161–2167 (2005).
- 30 . Biosynthesis of heme in mammals. Biochim. Biophys. Acta 1763(7), 723–736 (2006).
- 31 Humans possess two mitochondrial ferredoxins, Fdx1 and Fdx2, with distinct roles in steroidogenesis, heme, and Fe/S cluster biosynthesis. Proc. Natl Acad. Sci. USA 107(26), 11775–11780 (2010).
- 32 . Both human ferredoxins 1 and 2 and ferredoxin reductase are important for iron-sulfur cluster biogenesis. Biochim. Biophys. Acta 1823(2), 484–492 (2012).
- 33 . Metabolic regulation of citrate and iron by aconitases: role of iron-sulfur cluster biogenesis. Biometals 20(3–4), 549–564 (2007).
- 34 . Undetectable intracellular free copper: the requirement of a copper chaperone for superoxide dismutase. Science 284(5415), 805–808 (1999).
- 35 . Charting the travels of copper in eukaryotes from yeast to mammals. Biochim. Biophys. Acta 1823(9), 1580–1593 (2012).
- 36 . Copper metallochaperones. Annu. Rev. Biochem. 79, 537–562 (2010).
- 37 . Mitochondrial copper metabolism and delivery to cytochrome c oxidase. IUBMB Life 60(7), 421–429 (2008).
- 38 COX19 mediates the transduction of a mitochondrial redox signal from SCO1 that regulates ATP7A-mediated cellular copper efflux. Mol. Biol. Cell 24(6), 683–691 (2013).
- 39 . Different regulation of wild-type and mutant Cu, Zn superoxide dismutase localization in mammalian mitochondria. Hum. Mol. Genet. 17(21), 3303–3317 (2008).• Determined that mitochondrial localization of SOD1 is dependent upon oxygen concentration.
- 40 . Yeast contain a non-proteinaceous pool of copper in the mitochondrial matrix. J. Biol. Chem. 279(14), 14447–14455 (2004).
- 41 . Mitochondrial matrix copper complex used in metallation of cytochrome oxidase and superoxide dismutase. J. Biol. Chem. 281(48), 36552–36559 (2006).
- 42 . Superoxide dismutases: role in redox signaling, vascular function, and diseases. Antioxid. Redox Signal. 15(6), 1583–1606 (2011).
- 43 Modulation of mitochondrial function by endogenous Zn2+ pools. Proc. Natl Acad. Sci. USA 100(10), 6157–6162 (2003).
- 44 . Genetically encoded sensors to elucidate spatial distribution of cellular zinc. J. Biol. Chem. 284(24), 16289–16297 (2009).
- 45 New alternately colored FRET sensors for simultaneous monitoring of Zn(2)(+) in multiple cellular locations. PLoS One 7(11), e49371 (2012).
- 46 . New sensors for quantitative measurement of mitochondrial Zn(2+). ACS Chem. Biol. 7(10), 1636–1640 (2012).
- 47 . Zinc transporters and the cellular trafficking of zinc. Biochim. Biophys. Acta 1763(7), 711–722 (2006).
- 48 . Zim17, a novel zinc finger protein essential for protein import into mitochondria. J. Biol. Chem. 279(48), 50243–50249 (2004).
- 49 . Construction and testing of engineered zinc-finger proteins for sequence-specific modification of mtDNA. Nat. Protoc. 5(2), 342–356 (2010).
- 50 . Mitochondrially targeted ZFNs for selective degradation of pathogenic mitochondrial genomes bearing large-scale deletions or point mutations. EMBO Mol. Med. 6(4), 458–466 (2014).
- 51 . Clinical features and classification of inherited ataxias. Adv. Neurol. 61, 1–14 (1993).
- 52 . Clinical features of Friedreich's ataxia: classical and atypical phenotypes. J. Neurochem. 126(Suppl. 1), 103–117 (2013).
- 53 . Friedreich's ataxia: pathology, pathogenesis, and molecular genetics. J. Neurol. Sci. 303(1–2), 1–12 (2011).
- 54 . Friedreich ataxia: failure of GABA-ergic and glycinergic synaptic transmission in the dentate nucleus. J. Neuropathol. Exp. Neurol. 74(2), 166–176 (2015).
- 55 Inactivation of the Friedreich ataxia mouse gene leads to early embryonic lethality without iron accumulation. Hum. Mol. Genet. 9(8), 1219–1226 (2000).
- 56 Mammalian frataxin: an essential function for cellular viability through an interaction with a preformed ISCU/NFS1/ISD11 iron-sulfur assembly complex. PLoS One 6(1), e16199 (2011).• Demonstrated the role of frataxin in iron–sulfur cluster assembly.
- 57 Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia. Nat. Genet. 17(2), 215–217 (1997).
- 58 . Respiratory deficiency due to loss of mitochondrial DNA in yeast lacking the frataxin homologue. Nat. Genet. 16(4), 352–357 (1997).
- 59 . RNAi-mediated suppression of the mitochondrial iron chaperone, frataxin, in Drosophila. Hum. Mol. Genet. 14(22), 3397–3405 (2005).
- 60 Ancestral roles of eukaryotic frataxin: mitochondrial frataxin function and heterologous expression of hydrogenosomal trichomonas homologues in trypanosomes. Mol. Microbiol. 69(1), 94–109 (2008).
- 61 . Frataxin is essential for extramitochondrial Fe–S cluster proteins in mammalian tissues. Hum. Mol. Genet. 16(22), 2651–2658 (2007).
- 62 . Biogenesis of iron-sulfur clusters in mammalian cells: new insights and relevance to human disease. Dis. Model. Mech. 5(2), 155–164 (2012).
- 63 . Cytosolic iron-sulfur cluster assembly (CIA) system: factors, mechanism, and relevance to cellular iron regulation. J. Biol. Chem. 285(35), 26745–26751 (2010).
- 64 . Elucidation of the mechanism of mitochondrial iron loading in Friedreich's ataxia by analysis of a mouse mutant. Proc. Natl Acad. Sci. USA 106(38), 16381–16386 (2009).
- 65 Identification of nonferritin mitochondrial iron deposits in a mouse model of Friedreich ataxia. Proc. Natl Acad. Sci. USA 109(50), 20590–20595 (2012).
- 66 . Mitochondrial mayhem: the mitochondrion as a modulator of iron metabolism and its role in disease. Antioxid. Redox Signal. 15(12), 3003–3019 (2011).
- 67 . The yeast frataxin homologue mediates mitochondrial iron efflux. Evidence for a mitochondrial iron cycle. J. Biol. Chem. 274(8), 4497–4499 (1999).
- 68 Combined therapy with idebenone and deferiprone in patients with Friedreich's ataxia. Cerebellum 10(1), 1–8 (2011).
- 69 Selective iron chelation in Friedreich ataxia: biologic and clinical implications. Blood 110(1), 401–408 (2007).
- 70 . Increased iron in the dentate nucleus of patients with Friedrich's ataxia. Ann. Neurol. 46(1), 123–125 (1999).
- 71 . Dentate nuclei T2 relaxometry is a reliable neuroimaging marker in Friedreich's ataxia. Eur. J. Neurol. 21(8), 1131–1136 (2014).
- 72 . Transcranial sonography reveals cerebellar, nigral, and forebrain abnormalities in Friedreich's ataxia. Neurodegener. Dis. 8(6), 470–475 (2011).
- 73 Cerebellar pathology in Friedreich's ataxia: atrophied dentate nuclei with normal iron content. Neuroimage Clin. 6, 93–99 (2014).
- 74 . Clinical, biochemical and molecular genetic correlations in Friedreich's ataxia. Hum. Mol. Genet. 9(2), 275–282 (2000).
- 75 The dentate nucleus in Friedreich's ataxia: the role of iron-responsive proteins. Acta Neuropathol. 114(2), 163–173 (2007).
- 76 Friedreich's ataxia causes redistribution of iron, copper, and zinc in the dentate nucleus. Cerebellum 11(4), 845–860 (2012).
- 77 . Friedreich ataxia: metal dysmetabolism in dorsal root ganglia. Acta Neuropathol. Commun. 1(1), 26 (2013).
- 78 . Friedreich's ataxia: the vicious circle hypothesis revisited. BMC Med. 9, 112 (2011).
- 79 The Friedreich's ataxia mutation confers cellular sensitivity to oxidant stress which is rescued by chelators of iron and calcium and inhibitors of apoptosis. Hum. Mol. Genet. 8(3), 425–430 (1999).
- 80 . Frataxin expression rescues mitochondrial dysfunctions in FRDA cells. Hum. Mol. Genet. 10(19), 2099–2107 (2001).
- 81 The first cellular models based on frataxin missense mutations that reproduce spontaneously the defects associated with Friedreich ataxia. PLoS One 4(7), e6379 (2009).
- 82 Mouse models for Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and Fe–S enzyme deficiency followed by intramitochondrial iron deposits. Nat. Genet. 27(2), 181–186 (2001).
- 83 . Mitochondrial ferritin limits oxidative damage regulating mitochondrial iron availability: hypothesis for a protective role in Friedreich ataxia. Hum. Mol. Genet. 18(1), 1–11 (2009).
- 84 . Iron-dependent regulation of frataxin expression: implications for treatment of Friedreich ataxia. Hum. Mol. Genet. 17(15), 2265–2273 (2008).
- 85 . Redistribution of accumulated cell iron: a modality of chelation with therapeutic implications. Blood 111(3), 1690–1699 (2008).
- 86 Targeting chelatable iron as a therapeutic modality in Parkinson's disease. Antioxid. Redox Signal. 21(2), 195–210 (2014).• First study to demonstrate clinical efficacy of iron chelation for Parkinson's disease.
- 87 Deferiprone and idebenone rescue frataxin depletion phenotypes in a Drosophila model of Friedreich's ataxia. Gene 521(2), 274–281 (2013).
- 88 Cell functions impaired by frataxin deficiency are restored by drug-mediated iron relocation. Blood 112(13), 5219–5227 (2008).
- 89 Pharmacological screening using an FXN-EGFP cellular genomic reporter assay for the therapy of Friedreich ataxia. PloS One 8(2), e55940 (2013).
- 90 Deferiprone in Friedreich ataxia: a 6-month randomized controlled trial. Ann. Neurol. 76(4), 509–521 (2014).
- 91 . Overview of motor neuron disease: classification and nomenclature. Clin. Neurosci. 3(6), 323–326 (1995).
- 92 . The genetics and neuropathology of amyotrophic lateral sclerosis. Acta Neuropathol. 124(3), 339–352 (2012).
- 93 Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362(6415), 59–62 (1993).
- 94 . Dissection of genetic factors associated with amyotrophic lateral sclerosis. Exp. Neurol. 262(Pt B), 91–101 (2014).
- 95 . Genetic causes of amyotrophic lateral sclerosis: New genetic analysis methodologies entailing new opportunities and challenges. Brain Res. 1607, 75–93 (2015).
- 96 . Mitochondrial alterations in the spinal cord of patients with sporadic amyotrophic lateral sclerosis. J. Neuropathol. Exp. Neurol. 66(1), 10–16 (2007).
- 97 . Mitochondrial dysfunction and intracellular calcium dysregulation in ALS. Mech. Ageing Dev. 131(7–8), 517–526 (2010).
- 98 . Oxidative stress and mitochondrial damage: importance in non-SOD1 ALS. Front. Cell Neurosci. 9, 41 (2015).
- 99 A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement. Brain 137(Pt 8), 2329–2345 (2014).
- 100 Pathogenic VCP mutations induce mitochondrial uncoupling and reduced ATP levels. Neuron 78(1), 57–64 (2013).
- 101 Slow development of ALS-like spinal cord pathology in mutant valosin-containing protein gene knock-in mice. Cell Death Dis. 3, e374 (2012).
- 102 . Abnormal mitochondrial transport and morphology are common pathological denominators in SOD1 and TDP43 ALS mouse models. Hum. Mol. Genet. 23(6), 1413–1424 (2013).
- 103 The ALS disease-associated mutant TDP-43 impairs mitochondrial dynamics and function in motor neurons. Hum. Mol. Genet. 22(23), 4706–4719 (2013).
- 104 Entorhinal cortical neurons are the primary targets of FUS mislocalization and ubiquitin aggregation in FUS transgenic rats. Hum. Mol. Genet. 21(21), 4602–4614 (2012).
- 105 Defective mitochondrial dynamics is an early event in skeletal muscle of an amyotrophic lateral sclerosis mouse model. PLoS One 8(12), e82112 (2013).
- 106 Misfolded SOD1 associated with motor neuron mitochondria alters mitochondrial shape and distribution prior to clinical onset. PLoS One 6(7), e22031 (2011).
- 107 Characterization of early pathogenesis in the SOD1(G93A) mouse model of ALS: part II, results and discussion. Brain Behav. 3(4), 431–457 (2013).
- 108 Iron metabolism disturbance in a French cohort of ALS patients. Biomed. Res. Int. 2014, 485723 (2014).
- 109 Increased iron level in motor cortex of amyotrophic lateral sclerosis patients: an in vivo MR study. Amyotroph. Lateral Scler. Frontotemporal Degener. 15(5–6), 357–361 (2014).
- 110 Usefulness of SWI for the detection of iron in the motor cortex in amyotrophic lateral sclerosis. J. Neuroimaging 25(3), 443–451 (2014).
- 111 . Brain iron MRI: a biomarker for amyotrophic lateral sclerosis. J. Magn. Reson. Imaging 38(6), 1472–1479 (2013).
- 112 . Dysregulation of iron homeostasis in the CNS contributes to disease progression in a mouse model of amyotrophic lateral sclerosis. J. Neurosci. 29(3), 610–619 (2009).
- 113 Increased metal content in the TDP-43(A315T) transgenic mouse model of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Front. Aging Neurosci. 6, 15 (2014).
- 114 . Pathological roles of wild-type cu, zn-superoxide dismutase in amyotrophic lateral sclerosis. Neurol. Res. Int. 2012, 323261 (2012).
- 115 . Selective association of misfolded ALS-linked mutant SOD1 with the cytoplasmic face of mitochondria. Proc. Natl Acad. Sci. USA 105(10), 4022–4027 (2008).
- 116 Misfolded mutant SOD1 directly inhibits VDAC1 conductance in a mouse model of inherited ALS. Neuron 67(4), 575–587 (2010).
- 117 ALS-linked mutant superoxide dismutase 1 (SOD1) alters mitochondrial protein composition and decreases protein import. Proc. Natl Acad. Sci. USA 107(49), 21146–21151 (2010).
- 118 ALS-linked mutant SOD1 damages mitochondria by promoting conformational changes in Bcl-2. Hum. Mol. Genet. 19(15), 2974–2986 (2010).
- 119 SOD1 targeted to the mitochondrial intermembrane space prevents motor neuropathy in the Sod1 knockout mouse. Brain 134(Pt 1), 196–209 (2011).
- 120 Mutated human SOD1 causes dysfunction of oxidative phosphorylation in mitochondria of transgenic mice. J. Biol. Chem. 277(33), 29626–29633 (2002).
- 121 . CuZn superoxide dismutase (SOD1) accumulates in vacuolated mitochondria in transgenic mice expressing amyotrophic lateral sclerosis-linked SOD1 mutations. Acta Neuropathol. 102(4), 293–305 (2001).
- 122 In vivo pathogenic role of mutant SOD1 localized in the mitochondrial intermembrane space. J. Neurosci. 31(44), 15826–15837 (2011).
- 123 Enhancing mitochondrial calcium buffering capacity reduces aggregation of misfolded SOD1 and motor neuron cell death without extending survival in mouse models of inherited amyotrophic lateral sclerosis. J. Neurosci. 33(11), 4657–4671 (2013).
- 124 . A fraction of yeast Cu, Zn-superoxide dismutase and its metallochaperone, CCS, localize to the intermembrane space of mitochondria. A physiological role for SOD1 in guarding against mitochondrial oxidative damage. J. Biol. Chem. 276(41), 38084–38089 (2001).
- 125 . Factors controlling the uptake of yeast copper/zinc superoxide dismutase into mitochondria. J. Biol. Chem. 278(30), 28052–28059 (2003).
- 126 . Import, maturation, and function of SOD1 and its copper chaperone CCS in the mitochondrial intermembrane space. Antioxid. Redox Signal. 13(9), 1375–1384 (2010).
- 127 . Fibrillation precursor of superoxide dismutase 1 revealed by gradual tuning of the protein-folding equilibrium. Proc. Natl Acad. Sci. USA 109(44), 17868–17873 (2012).• Demonstrated that SOD1 aggregation is driven by the unfolded immature monomer.
- 128 . Variation in aggregation propensities among ALS-associated variants of SOD1: correlation to human disease. Hum. Mol. Genet. 18(17), 3217–3226 (2009).
- 129 A comprehensive assessment of the SOD1G93A low-copy transgenic mouse, which models human amyotrophic lateral sclerosis. Dis. Model. Mech. 4(5), 686–700 (2011).
- 130 . Phenotype of transgenic mice carrying a very low copy number of the mutant human G93A superoxide dismutase-1 gene associated with amyotrophic lateral sclerosis. PLoS One 9(6), e99879 (2014).
- 131 Human Cu/Zn superoxide dismutase (SOD1) overexpression in mice causes mitochondrial vacuolization, axonal degeneration, and premature motoneuron death and accelerates motoneuron disease in mice expressing a familial amyotrophic lateral sclerosis mutant SOD1. Neurobiol. Dis. 7(6 Pt B), 623–643 (2000).
- 132 Expression of wild-type human superoxide dismutase-1 in mice causes amyotrophic lateral sclerosis. Hum. Mol. Genet. 22(1), 51–60 (2013).
- 133 Disulphide-reduced superoxide dismutase-1 in CNS of transgenic amyotrophic lateral sclerosis models. Brain 129(Pt 2), 451–464 (2006).
- 134 Isolated cytochrome c oxidase deficiency in G93A SOD1 mice overexpressing CCS protein. J. Biol. Chem. 283(18), 12267–12275 (2008).
- 135 Overexpression of CCS in G93A-SOD1 mice leads to accelerated neurological deficits with severe mitochondrial pathology. Proc. Natl Acad. Sci. USA 104(14), 6072–6077 (2007).
- 136 . Expression of zinc-deficient human superoxide dismutase in Drosophila neurons produces a locomotor defect linked to mitochondrial dysfunction. Neurobiol. Aging 34(10), 2322–2330 (2013).
- 137 Dysregulation of iron protein expression in the G93A model of amyotrophic lateral sclerosis. Neuroscience 230, 94–101 (2013).
- 138 Prevention of motor neuron degeneration by novel iron chelators in SOD1(G93A) transgenic mice of amyotrophic lateral sclerosis. Neurodegener. Dis. 8(5), 310–321 (2011).
- 139 Diacetylbis(N(4)-methylthiosemicarbazonato) copper(II) (CuII(atsm)) protects against peroxynitrite-induced nitrosative damage and prolongs survival in amyotrophic lateral sclerosis mouse model. J. Biol. Chem. 286(51), 44035–44044 (2011).
- 140 Therapeutic effects of Cu(II)(atsm) in the SOD1-G37R mouse model of amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. Frontotemporal Degener. 14(7–8), 586–590 (2013).
- 141 Oral treatment with CuII(atsm) increases mutant SOD1 in vivo but protects motor neurons and improves the phenotype of a transgenic mouse model of amyotrophic lateral sclerosis. J. Neurosci. 34(23), 8021–8031 (2014).• CuII(atsm) delays the onset of amyotrophic lateral sclerosis symptoms in mice via delivery of copper to SOD1.
- 142 Cu-ATSM: an effective treatment for high-expressing G93A-SOD1 mice expressing the human copper chaperone for SOD1 (CCS). Amyotroph. Lateral Scler. Frontotemporal Degener. 15(S1), 45 (2014).
- 143 . Neuroprotective and neuritogenic activities of novel multimodal iron-chelating drugs in motor-neuron-like NSC-34 cells and transgenic mouse model of amyotrophic lateral sclerosis. FASEB J. 23(11), 3766–3779 (2009).
- 144 Design, synthesis, and evaluation of novel bifunctional iron-chelators as potential agents for neuroprotection in Alzheimer's, Parkinson's, and other neurodegenerative diseases. Bioorg. Med. Chem. 13(3), 773–783 (2005).
- 145 . Zinc inhibition of BMAA toxicity. Amyotroph. Lateral Scler. 12(Suppl. 1), 165 (2011).
- 146 . Axonal transport and mitochondrial dysfunction in Alzheimer's disease. Neurodegener. Dis. 12(3), 111–124 (2013).
- 147 Atherosclerotic lesions and mitochondria DNA deletions in brain microvessels as a central target for the development of human AD and AD-like pathology in aged transgenic mice. Ann. NY Acad. Sci. 977, 45–64 (2002).
- 148 Mitochondrial abnormalities in Alzheimer's disease. J. Neurosci. 21(9), 3017–3023 (2001).
- 149 Brain cytochrome oxidase in Alzheimer's disease. J. Neurochem. 59(2), 776–779 (1992).
- 150 . Cortical cytochrome oxidase activity is reduced in Alzheimer's disease. J. Neurochem. 63(6), 2179–2184 (1994).
- 151 . A selective defect of cytochrome c oxidase is present in brain of Alzheimer disease patients. Neurobiol. Aging 21(3), 455–462 (2000).
- 152 . Mitochondrial DNA deletions in Alzheimer's brains: a review. Alzheimers Dement. 10(3), 393–400 (2014).
- 153 Mitochondrial dysfunction: an early event in Alzheimer pathology accumulates with age in AD transgenic mice. Neurobiol. Aging 30(10), 1574–1586 (2009).
- 154 . Quantitative proteomic analysis of mitochondria in aging PS-1 transgenic mice. Cell Mol. Neurobiol. 29(5), 649–664 (2009).
- 155 . Mitochondrial dysfunction is a trigger of Alzheimer's disease pathophysiology. Biochim. Biophys. Acta 1802(1), 2–10 (2010).
- 156 Impaired short-term plasticity in mossy fiber synapses caused by mitochondrial dysfunction of dentate granule cells is the earliest synaptic deficit in a mouse model of Alzheimer's disease. J. Neurosci. 32(17), 5953–5963 (2012).
- 157 . Mitochondria are a direct site of A beta accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum. Mol. Genet. 15(9), 1437–1449 (2006).
- 158 ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease. Science 304(5669), 448–452 (2004).
- 159 Copper-dependent inhibition of human cytochrome c oxidase by a dimeric conformer of amyloid-beta1–42. J. Neurosci. 25(3), 672–679 (2005).
- 160 . Biometals and their therapeutic implications in Alzheimer's disease. Neurotherapeutics 12(1), 109–120 (2014).
- 161 In vivo evaluation of brain iron in Alzheimer's disease and normal subjects using MRI. Biol. Psychiatry 35(7), 480–487 (1994).
- 162 Ribosomal RNA in Alzheimer disease is oxidized by bound redox-active iron. J. Biol. Chem. 280(22), 20978–20986 (2005).
- 163 . Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc. Natl Acad. Sci. USA 94(18), 9866–9868 (1997).
- 164 . Iron, zinc and copper in the Alzheimer's disease brain: a quantitative meta-analysis. Some insight on the influence of citation bias on scientific opinion. Prog. Neurobiol. 94(3), 296–306 (2011).
- 165 Decreased copper in Alzheimer's disease brain is predominantly in the soluble extractable fraction. Int. J. Alzheimers Dis. 2013, 623241 (2013).
- 166 . Synchrotron-based infrared and X-ray imaging shows focalized accumulation of Cu and Zn co-localized with beta-amyloid deposits in Alzheimer's disease. J. Struct. Biol. 155(1), 30–37 (2006).
- 167 Ceruloplasmin dysfunction and therapeutic potential for Parkinson disease. Ann. Neurol. 73(4), 554–559 (2013).
- 168 . beta-amyloid precursor protein does not possess ferroxidase activity but does stabilize the cell surface ferrous iron exporter ferroportin. PLoS One 9(12), e114174 (2014).
- 169 Iron-export ferroxidase activity of beta-amyloid precursor protein is inhibited by zinc in Alzheimer's disease. Cell 142(6), 857–867 (2010).
- 170 Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nat. Med. 18(2), 291–295 (2012).
- 171 Mitochondrial ferritin attenuates beta-amyloid-induced neurotoxicity: reduction in oxidative damage through the Erk/P38 mitogen-activated protein kinase pathways. Antioxid. Redox Signal. 18(2), 158–169 (2013).
- 172 Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta. Neuron 59(1), 43–55 (2008).
- 173 Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice. Neuron 30(3), 665–676 (2001).
- 174 Degradation of the Alzheimer disease amyloid beta-peptide by metal-dependent up-regulation of metalloprotease activity. J. Biol. Chem. 281(26), 17670–17680 (2006).• Discovered metal ionophore mechanism of action for clioquinol.
- 175 The Alzheimer's therapeutic PBT2 promotes amyloid-beta degradation and GSK3 phosphorylation via a metal chaperone activity. J. Neurochem. 119(1), 220–230 (2011).
- 176 Clioquinol rescues parkinsonism and dementia phenotypes of the tau knockout mouse. Neurobiol. Dis. (In Press) (2015).
- 177 Pyrrolidine dithiocarbamate activates Akt and improves spatial learning in APP/PS1 mice without affecting beta-amyloid burden. J. Neurosci. 27(14), 3712–3721 (2007).
- 178 . The novel multi-target iron chelating-radical scavenging compound M30 possesses beneficial effects on major hallmarks of Alzheimer's disease. Antioxid. Redox Signal. 17(6), 860–877 (2012).
- 179 Enhanced brain delivery of deferasirox-lactoferrin conjugates for iron chelation therapy in neurodegenerative disorders: in vitro and in vivo studies. Mol. Pharm. 10(12), 4418–4431 (2013).
- 180 Increasing Cu bioavailability inhibits Abeta oligomers and tau phosphorylation. Proc. Natl Acad. Sci. USA 106(2), 381–386 (2009).
- 181 Intramuscular desferrioxamine in patients with Alzheimer's disease. Lancet 337(8753), 1304–1308 (1991).
- 182 Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch. Neurol. 60(12), 1685–1691 (2003).
- 183 Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer's disease: a Phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 7(9), 779–786 (2008).
- 184 PBT2 rapidly improves cognition in Alzheimer's disease: additional phase II analyses. J. Alzheimers Dis. 20(2), 509–516 (2010).
- 185 . Neurodegenerative processes in Huntington's disease. Cell Death Dis. 2, e228 (2011).
- 186 . Metabolism in HD: still a relevant mechanism? Mov. Disord. 29(11), 1366–1374 (2014).
- 187 . Iron dysregulation in Huntington's disease. J. Neurochem. 130(3), 328–350 (2014).
- 188 Alterations in the levels of iron, ferritin and other trace metals in Parkinson's disease and other neurodegenerative diseases affecting the basal ganglia. Brain 114(Pt 4), 1953–1975 (1991).
- 189 Increased regional brain concentrations of ceruloplasmin in neurodegenerative disorders. Brain Res. 738(2), 265–274 (1996).
- 190 Alterations in brain transition metals in Huntington disease: an evolving and intricate story. Arch. Neurol. 69(7), 887–893 (2012).
- 191 Mechanisms of copper ion mediated Huntington's disease progression. PLoS One 2(3), e334 (2007).
- 192 Iron accumulates in Huntington's disease neurons: protection by deferoxamine. PLoS One 8(10), e77023 (2013).
- 193 . Changes in transition metal contents in rat brain regions after in vivo quinolinate intrastriatal administration. Arch. Med. Res. 27(4), 449–452 (1996).
- 194 Sub-chronic copper pretreatment reduces oxidative damage in an experimental Huntington's disease model. Biol. Trace Elem. Res. 162(1–3), 211–218 (2014).
- 195 Regional and cellular gene expression changes in human Huntington's disease brain. Hum. Mol. Genet. 15(6), 965–977 (2006).
- 196 . Huntingtin: an iron-regulated protein essential for normal nuclear and perinuclear organelles. Hum. Mol. Genet. 9(19), 2789–2797 (2000).
- 197 . Mitochondrial inhibitor models of Huntington's disease and Parkinson's disease induce zinc accumulation and are attenuated by inhibition of zinc neurotoxicity in vitro or in vivo. Neurodegener. Dis. 11(1), 49–58 (2013).
- 198 . PBT2 reduces toxicity in a C. elegans model of polyq aggregation and extends lifespan, reduces striatal atrophy and improves motor performance in the R6/2 mouse model of Huntington's disease. J. Huntingtons Dis. 1(2), 211–219 (2012).
- 199 Investigators HSGRH. Safety, tolerability, and efficacy of PBT2 in Huntington's disease: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 14(1), 39–47 (2015).
- 200 The etiopathogenesis of Parkinson disease and suggestions for future research. Part II. J. Neuropathol. Exp. Neurol. 66(5), 329–336 (2007).
- 201 . Alpha-synuclein in Lewy bodies. Nature 388(6645), 839–840 (1997).
- 202 . Alpha-synuclein and neurodegenerative diseases. Nat. Rev. Neurosci. 2(7), 492–501 (2001).
- 203 . Mitochondrial complex I deficiency in Parkinson's disease. Lancet 1(8649), 1269 (1989).
- 204 Deficiencies in complex I subunits of the respiratory chain in Parkinson's disease. Biochem. Biophys. Res. Commun. 163(3), 1450–1455 (1989).
- 205 Rotenone, paraquat, and Parkinson's disease. Environ. Health Perspect. 119(6), 866–872 (2011).
- 206 . Nigral iron elevation is an invariable feature of Parkinson's disease and is a sufficient cause of neurodegeneration. Biomed. Res. Int. 2014, 581256 (2014).
- 207 Mapping metals in Parkinson's and normal brain using rapid-scanning x-ray fluorescence. Phys. Med. Biol. 54(3), 651–663 (2009).
- 208 Copper pathology in vulnerable brain regions in Parkinson's disease. Neurobiol. Aging 35(4), 858–866 (2014).
- 209 Iron accumulation in the substantia nigra of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced hemiparkinsonian monkeys. Neurosci. Lett. 168(1–2), 251–253 (1994).
- 210 . Increased iron in the substantia nigra compacta of the MPTP-lesioned hemiparkinsonian African green monkey: evidence from proton microprobe elemental microanalysis. J. Neurochem. 62(1), 134–146 (1994).
- 211 Transferrin receptor 2: continued expression in mouse liver in the face of iron overload and in hereditary hemochromatosis. Proc. Natl Acad. Sci. USA 97(5), 2214–2219 (2000).
- 212 Inhibition of prolyl hydroxylase protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity: model for the potential involvement of the hypoxia-inducible factor pathway in Parkinson disease. J. Biol. Chem. 284(42), 29065–29076 (2009).
- 213 A novel transferrin/TfR2-mediated mitochondrial iron transport system is disrupted in Parkinson's disease. Neurobiol. Dis. 34(3), 417–431 (2009).
- 214 . Degeneration of nigrostriatal dopaminergic neurons increases iron within the substantia nigra: a histochemical and neurochemical study. Brain Res. 660(1), 8–18 (1994).
- 215 . Depletion of copper and manganese in brain after MPTP treatment of mice. Pharmacol. Toxicol. 76(6), 348–352 (1995).
- 216 . Astrocyte mitochondria: a substrate for iron deposition in the aging rat substantia nigra. Exp. Neurol. 152(2), 188–196 (1998).
- 217 Alterations in glutathione levels in Parkinson's disease and other neurodegenerative disorders affecting basal ganglia. Ann. Neurol. 36(3), 348–355 (1994).
- 218 . Alterations in the distribution of glutathione in the substantia nigra in Parkinson's disease. J. Neural Transm. 104(6–7), 661–677 (1997).
- 219 . Glutathione – a review on its role and significance in Parkinson's disease. FASEB J. 23(10), 3263–3272 (2009).
- 220 . A disruption in iron-sulfur center biogenesis via inhibition of mitochondrial dithiol glutaredoxin 2 may contribute to mitochondrial and cellular iron dysregulation in mammalian glutathione-depleted dopaminergic cells: implications for Parkinson's disease. Antioxid. Redox Signal. 11(9), 2083–2094 (2009).
- 221 . Parkinson's disease-associated human ATP13A2 (PARK9) deficiency causes zinc dyshomeostasis and mitochondrial dysfunction. Hum. Mol. Genet. 23(11), 2802–2815 (2014).
- 222 Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: a novel therapy for Parkinson's disease. Neuron 37(6), 899–909 (2003).
- 223 Neuroprotective mechanism of mitochondrial ferritin on 6-hydroxydopamine-induced dopaminergic cell damage: implication for neuroprotection in Parkinson's disease. Antioxid. Redox Signal. 13(6), 783–796 (2010).
- 224 . Neuroprotective effect of the iron chelator desferrioxamine against MPP+ toxicity on striatal dopaminergic terminals. J. Neurochem. 68(2), 732–738 (1997).
- 225 . The iron chelator desferrioxamine (Desferal) retards 6-hydroxydopamine-induced degeneration of nigrostriatal dopamine neurons. J. Neurochem. 56(4), 1441–1444 (1991).
- 226 . Role of iron and iron chelation in dopaminergic-induced neurodegeneration: implication for Parkinson's disease. Ann. Neurol. 32(Suppl.), S105–110 (1992).
- 227 . Desferrioxamine and vitamin E protect against iron and MPTP-induced neurodegeneration in mice. J. Neural Transm. 104(4–5), 469–481 (1997).
- 228 . Neuroprotection of desferrioxamine in lipopolysaccharide-induced nigrostriatal dopamine neuron degeneration. Mol. Med. Report. 5(2), 562–566 (2012).
- 229 Clinically available iron chelators induce neuroprotection in the 6-OHDA model of Parkinson's disease after peripheral administration. J. Neural Transm. 118(2), 223–231 (2011).
- 230 Lipophilic adamantyl- or deferasirox-based conjugates of desferrioxamine B have enhanced neuroprotective capacity: implications for Parkinson disease. Free. Radic. Biol. Med. 60, 147–156 (2013).
- 231 . Neuroprotective effect of acute and chronic administration of copper (II) sulfate against MPP+ neurotoxicity in mice. Neurochem. Res. 26(1), 59–64 (2001).
- 232 . The copper chelator, D-penicillamine, does not attenuate MPTP induced dopamine depletion in mice. J. Neural Transm. 114(2), 205–209 (2007).
- 233 The hypoxia imaging agent CuII(atsm) is neuroprotective and improves motor and cognitive functions in multiple animal models of Parkinson's disease. J. Exp. Med. 209(4), 837–854 (2012).
- 234 . Neuroprotection by a novel brain permeable iron chelator, VK-28, against 6-hydroxydopamine lession in rats. Neuropharmacology 46(2), 254–263 (2004).
- 235 . Novel multifunctional neuroprotective iron chelator-monoamine oxidase inhibitor drugs for neurodegenerative diseases. In vivo selective brain monoamine oxidase inhibition and prevention of MPTP-induced striatal dopamine depletion. J. Neurochem. 95(1), 79–88 (2005).
- 236 . Restoration of nigrostriatal dopamine neurons in post-MPTP treatment by the novel multifunctional brain-permeable iron chelator-monoamine oxidase inhibitor drug, M30. Neurotox. Res. 17(1), 15–27 (2010).
- 237 . The novel multi-target iron chelator, M30 modulates HIF-1alpha-related glycolytic genes and insulin signaling pathway in the frontal cortex of APP/PS1 Alzheimer's disease mice. Curr. Alzheimer Res. 11(2), 119–127 (2014).