Advertisement

Manganese and the Insulin-IGF Signaling Network in Huntington’s Disease and Other Neurodegenerative Disorders

  • Miles R. BryanEmail author
  • Aaron B. Bowman
Chapter
Part of the Advances in Neurobiology book series (NEUROBIOL, volume 18)

Abstract

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease resulting in motor impairment and death in patients. Recently, several studies have demonstrated insulin or insulin-like growth factor (IGF) treatment in models of HD, resulting in potent amelioration of HD phenotypes via modulation of the PI3K/AKT/mTOR pathways. Administration of IGF and insulin can rescue microtubule transport, metabolic function, and autophagy defects, resulting in clearance of Huntingtin (HTT) aggregates, restoration of mitochondrial function, amelioration of motor abnormalities, and enhanced survival. Manganese (Mn) is an essential metal to all biological systems but, in excess, can be toxic. Interestingly, several studies have revealed the insulin-mimetic effects of Mn—demonstrating Mn can activate several of the same metabolic kinases and increase peripheral and neuronal insulin and IGF-1 levels in rodent models. Separate studies have shown mouse and human striatal neuroprogenitor cell (NPC) models exhibit a deficit in cellular Mn uptake, indicative of a Mn deficiency. Furthermore, evidence from the literature reveals a striking overlap between cellular consequences of Mn deficiency (i.e., impaired function of Mn-dependent enzymes) and known HD endophenotypes including excitotoxicity, increased reactive oxygen species (ROS) accumulation, and decreased mitochondrial function. Here we review published evidence supporting a hypothesis that (1) the potent effect of IGF or insulin treatment on HD models, (2) the insulin-mimetic effects of Mn, and (3) the newly discovered Mn-dependent perturbations in HD may all be functionally related. Together, this review will present the intriguing possibility that intricate regulatory cross-talk exists between Mn biology and/or toxicology and the insulin/IGF signaling pathways which may be deeply connected to HD pathology and, perhaps, other neurodegenerative diseases (NDDs) and other neuropathological conditions.

Keywords

Neuroprogenitor cell (NPC) Autophagy Mitochondria Cargo recognition Dysregulation 

References

  1. Åberg D, Johansson P, Isgaard J, Wallin A, Johansson J-O, Andreasson U, Blennow K, Zetterberg H, Åberg DN, Svensson J. Increased cerebrospinal fluid level of insulin-like growth factor-II in male patients with Alzheimer’s disease. Journal of Alzheimer’s disease : JAD. 2015;48(3):637–46.PubMedCrossRefGoogle Scholar
  2. Adem A, Ekblom J, Gillberg PG, Jossan SS, Höög A, Winblad B, Aquilonius SM, Wang LH, Sara V. Insulin-like growth factor-1 receptors in human spinal cord: changes in amyotrophic lateral sclerosis. J Neural Transm. 1994;97(1):73–84.CrossRefGoogle Scholar
  3. Aleman I. Insulin-like growth factor-1 and central neurodegenerative diseases. Endocrinol Metab Clin N Am. 2012;41(2):395–408.CrossRefGoogle Scholar
  4. Alexi T, Hughes PE, van Roon-Mom WM, Faull RL, Williams CE, Clark RG, Gluckman PD. The IGF-I amino-terminal tripeptide glycine-proline-glutamate (GPE) is neuroprotective to striatum in the quinolinic acid lesion animal model of Huntington’s disease. Exp Neurol. 1999;159(1):84–97.PubMedCrossRefGoogle Scholar
  5. Allodi I, Comley L, Nichterwitz S, Nizzardo M, Simone C, Benitez JA, Cao M, Corti S, Hedlund E. Differential neuronal vulnerability identifies IGF-2 as a protective factor in ALS. Sci Rep. 2016;6:25960.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Andreassen OA, Dedeoglu A, Ferrante RJ, Jenkins BG, Ferrante KL, Thomas M, Friedlich A, Browne SE, Schilling G, Borchelt DR, Hersch SM, Ross CA, Beal MF. Creatine increase survival and delays motor symptoms in a transgenic animal model of Huntington’s disease. Neurobiol Dis. 2001;8(3):479–91.PubMedCrossRefGoogle Scholar
  7. Arrasate M, Finkbeiner S. Protein aggregates in Huntington’s disease. Exp Neurol. 2011;238(1):1–11.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Aschner M, Erikson KM, Hernández E, Hernández E, Tjalkens R. Manganese and its role in Parkinson’s disease: from transport to neuropathology. NeuroMolecular Med. 2009;11(4):252–66.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Ayadi AE, Zigmond MJ, Smith AD. IGF-1 protects dopamine neurons against oxidative stress: association with changes in phosphokinases. Exp Brain Res. 2016;234(7):1863–73.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Bae J-H, Jang B-C, Suh S-I, Ha E, Baik H, Kim S-S, Lee M-y, Shin D-H. Manganese induces inducible nitric oxide synthase (iNOS) expression via activation of both MAP kinase and PI3K/Akt pathways in BV2 microglial cells. Neurosci Lett. 2006;398(1–2):151–4.PubMedCrossRefGoogle Scholar
  11. Baly DL (1984). Effect of manganese deficiency on insulin secretion and carbohydrate Heomostasis in rats. JNutrition.Google Scholar
  12. Baly DL, Keen CL, Hurley LS. Effects of manganese deficiency on pyruvate carboxylase and phosphoenolpyruvate carboxykinase activity and carbohydrate homeostasis in adult rats. Biol Trace Elem Res. 1986;11(1):201–12.PubMedCrossRefGoogle Scholar
  13. Baly DL, Lee I, Doshi R. Mechanism of decreased insulinogenesis in manganese-deficient rats. Decreased insulin mRNA levels. FEBS Lett. 1988;239(1):55–8.PubMedCrossRefGoogle Scholar
  14. Baly DL, Schneiderman JS, Garcia-Welsh AL. Effect of manganese deficiency on insulin binding, glucose transport and metabolism in rat adipocytes. J Nutr. 1990;120(9):1075–9.PubMedGoogle Scholar
  15. Bandmann O, Weiss K, Kaler SG. Wilson’s disease and other neurological copper disorders. The Lancet Neurology. 2015;14(1):103–13.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Bano D, Zanetti F, Mende Y, Nicotera P. Neurodegenerative processes in Huntington’s disease. Cell Death Dis. 2011;2(11)Google Scholar
  17. Bassil F, Fernagut P-O, Bezard E, Meissner WG. Insulin, IGF-1 and GLP-1 signaling in neurodegenerative disorders: targets for disease modification? Prog Neurobiol. 2014;118:1–18.PubMedCrossRefGoogle Scholar
  18. Bates G, Tabrizi S and Jones L (2014). Huntington’s disease. Huntington’s disease.Google Scholar
  19. Bates GP, Dorsey R, Gusella JF, Hayden MR, Kay C, Leavitt BR, Nance M, Ross CA, Scahill RI, Wetzel R, Wild EJ and Tabrizi SJ (2015). Huntington disease. Nature reviews Disease primers. 1: 15005.Google Scholar
  20. Baxter RC. IGF binding proteins in cancer: mechanistic and clinical insights. Nat Rev Cancer. 2014;14(5):329–41.PubMedCrossRefGoogle Scholar
  21. Behrend L, Mohr A, Dick T, Zwacka RM. Manganese superoxide dismutase induces p53-dependent senescence in colorectal cancer cells. Mol Cell Biol. 2005;25(17):7758–69.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Bernhard FP, Heinzel S, Binder G, Weber K, Apel A, Roeben B, Deuschle C, Maechtel M, Heger T, Nussbaum S, Gasser T, Maetzler W, Berg D. Insulin-like growth factor 1 (IGF-1) in Parkinson’s disease: potential as trait-, progression- and prediction marker and confounding factors. PLoS One. 2016;11(3)Google Scholar
  23. Bhat MA, Rios JC, Lu Y, Garcia-Fresco GP, Ching W, Martin M, Li J, Einheber S, Chesler M, Rosenbluth J, Salzer JL, Bellen HJ. Axon-glia interactions and the domain Organization of Myelinated Axons Requires Neurexin IV/Caspr/Paranodin. Neuron. 2001;30(2):369–83.PubMedCrossRefGoogle Scholar
  24. Bilic E, Bilic E, Rudan I, Kusec V, Zurak N, Delimar D, Zagar M. Comparison of the growth hormone, IGF-1 and insulin in cerebrospinal fluid and serum between patients with motor neuron disease and healthy controls. Eur J Neurol. 2006;13(12):1340–5.PubMedCrossRefGoogle Scholar
  25. Blázquez C, Chiarlone A, Bellocchio L, Resel E, Pruunsild P, García-Rincón D, Sendtner M, Timmusk T, Lutz B, Galve-Roperh I, Guzmán M. The CB1 cannabinoid receptor signals striatal neuroprotection via a PI3K/Akt/mTORC1/BDNF pathway. Cell Death Differ. 2015;22(10):1618–29.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Borasio GD, Robberecht W, Leigh PN, Emile J, Guiloff RJ, Jerusalem F, Silani V, Vos PE, Wokke JH, Dobbins T. A placebo-controlled trial of insulin-like growth factor-I in amyotrophic lateral sclerosis. European ALS/IGF-I study group. Neurology. 1998;51(2):583–6.PubMedCrossRefGoogle Scholar
  27. Bowman AB, Kwakye GF, Hernández E, Aschner M. Role of manganese in neurodegenerative diseases. J Trace Elem Med Biol. 2011;25(4):191–203.PubMedPubMedCentralCrossRefGoogle Scholar
  28. Cattaneo E, Zuccato C, Tartari M. Normal huntingtin function: an alternative approach to Huntington’s disease. Nat Rev Neurosci. 2005;6(12):919–30.PubMedCrossRefGoogle Scholar
  29. Cersosimo MG, Koller WC. The diagnosis of manganese-induced parkinsonism. Neurotoxicology. 2005;27(3):340–6.PubMedCrossRefGoogle Scholar
  30. Chan DW, Son SC, Block W, Ye R, Khanna KK, Wold MS, Douglas P, Goodarzi AA, Pelley J, Taya Y, Lavin MF, Lees-Miller SP. Purification and characterization of ATM from human placenta. A manganese-dependent, wortmannin-sensitive serine/threonine protein kinase. J Biol Chem. 2000;275(11):7803–10.PubMedCrossRefGoogle Scholar
  31. Chen S, Zhang X, Song L, Le W. Autophagy dysregulation in amyotrophic lateral sclerosis. Brain Pathol. 2012;22(1):110–6.PubMedCrossRefGoogle Scholar
  32. Chen P, Chakraborty S, Mukhopadhyay S, Lee E, Paoliello MM, Bowman AB, Aschner M. Manganese homeostasis in the nervous system. J Neurochem. 2015;134(4):601–10.PubMedPubMedCentralCrossRefGoogle Scholar
  33. Ching J, Luebbert SH, Zhang Z, Marupudi N, Banerjee S, Hurd R, Collins IV, Roy L, Ralston L and Fisher JS (2009). Ataxia telangiectasia mutated (ATM) is required in insulin-like growth factor-1 (IGF-1) signaling through the PI3K/Akt pathway. FASEB J. 23.Google Scholar
  34. Chinta SJ, Mallajosyula JK, Rane A, Andersen JK. Mitochondrial α-synuclein accumulation impairs complex I function in dopaminergic neurons and results in increased mitophagy in vivo. Neurosci Lett. 2010;486(3):235–9.PubMedPubMedCentralCrossRefGoogle Scholar
  35. Chitnis MM, Lodhia KA, Aleksic T, Gao S, Protheroe AS, Macaulay VM. IGF-1R inhibition enhances radiosensitivity and delays double-strand break repair by both non-homologous end-joining and homologous recombination. Oncogene. 2014;33(45):5262–73.PubMedCrossRefGoogle Scholar
  36. Chiu S-L, Chen C-M, Cline HT. Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo. Neuron. 2008;58(5):708–19.PubMedPubMedCentralCrossRefGoogle Scholar
  37. Chui D, Yang H, Wang H, Tuo JI, Yu J, Zhang S, Chen Z, Xiao W. The dishomeostasis of metal ions plays an important role for the cognitive impartment. Mol Neurodegener. 2013;8(S1):1–1.Google Scholar
  38. Ciucci F, Putignano E, Baroncelli L, Landi S, Berardi N, Maffei L. Insulin-like growth factor 1 (IGF-1) mediates the effects of enriched environment (EE) on visual cortical development. PLoS One. 2007;2(5)Google Scholar
  39. Clegg MS, Donovan SM, Monaco MH, Baly DL, Ensunsa JL, Keen CL. The influence of manganese deficiency on serum IGF-1 and IGF binding proteins in the male rat. Proc Soc Exp Biol Med Soc Exper Biol Med NY. 1998;219(1):41–7.CrossRefGoogle Scholar
  40. Clemmons DR, Busby WH, Arai T, Nam TJ, Clarke JB, Jones JI, Ankrapp DK. Role of insulin-like growth factor binding proteins in the control of IGF actions. Prog Growth Factor Res. 1995;6(2–4):357–66.PubMedCrossRefGoogle Scholar
  41. Cohen E, Paulsson JF, Blinder P, Burstyn-Cohen T, Du D, Estepa G, Adame A, Pham HM, Holzenberger M, Kelly JW, Masliah E, Dillin A. Reduced IGF-1 signaling delays age-associated Proteotoxicity in mice. Cell. 2009;139(6):1157–69.PubMedPubMedCentralCrossRefGoogle Scholar
  42. Cohen E, Du D, Joyce D, Kapernick EA, Volovik Y, Kelly JW, Dillin A. Temporal requirements of insulin/IGF-1 signaling for proteotoxicity protection. Aging Cell. 2010;9(2):126–34.PubMedPubMedCentralCrossRefGoogle Scholar
  43. Cordova FM, Aguiar AS, Peres TV, Lopes MW, Gonçalves FM, Remor AP, Lopes SC, Pilati C, Latini AS, Prediger RD, Erikson KM, Aschner M, Leal RB. In vivo manganese exposure modulates Erk, Akt and Darpp-32 in the striatum of developing rats, and impairs their motor function. PLoS One. 2012;7(3)Google Scholar
  44. Cordova FM, Aguiar AS, Peres TV, Lopes MW, Gonçalves FM, Pedro DZ, Lopes SC, Pilati C, Prediger RD, Farina M, Erikson KM, Aschner M, Leal RB. Manganese-exposed developing rats display motor deficits and striatal oxidative stress that are reversed by Trolox. Arch Toxicol. 2013;87(7):1231–44.PubMedCrossRefGoogle Scholar
  45. Cortes CJ, Spada AR. The many faces of autophagy dysfunction in Huntington’s disease: from mechanism to therapy. Drug Discov Today. 2014;19(7):963–71.PubMedPubMedCentralCrossRefGoogle Scholar
  46. Craft S, Watson GS. Insulin and neurodegenerative disease: shared and specific mechanisms. The Lancet Neurology. 2004;3(3):169–78.PubMedCrossRefGoogle Scholar
  47. Crittenden PL, Filipov NM. Manganese modulation of MAPK pathways: effects on upstream mitogen activated protein kinase kinases and mitogen activated kinase phosphatase-1 in microglial cells. Journal of applied toxicology : JAT. 2011;31(1):1–10.PubMedPubMedCentralCrossRefGoogle Scholar
  48. Cuervo A, Zhang S. Selective autophagy and huntingtin: learning from disease. Cell Cycle. 2015;14(11)Google Scholar
  49. D’Antonio EL, Hai Y, Christianson DW. Structure and function of non-native metal clusters in human arginase I. Biochemistry. 2012;51(42):8399–409.PubMedPubMedCentralCrossRefGoogle Scholar
  50. D’Ercole AJ, Ye P, Calikoglu AS, Gutierrez-Ospina G. The role of the insulin-like growth factors in the central nervous system. Mol Neurobiol. 1996;13(3):227–55.PubMedCrossRefGoogle Scholar
  51. D’Ercole JA, Ye P, O’Kusky JR. Mutant mouse models of insulin-like growth factor actions in the central nervous system. Neuropeptides. 2002;36(2–3):209–20.PubMedCrossRefGoogle Scholar
  52. Damiano M, Galvan L, Déglon N, Brouillet E. Mitochondria in Huntington’s disease. Biochim Biophys Acta (BBA) - Mol Basis Dis. 2010;1802(1):52–61.CrossRefGoogle Scholar
  53. Dearth RK, Hiney JK, Srivastava VK, Hamilton AM, Dees WL. Prepubertal exposure to elevated manganese results in estradiol regulated mammary gland ductal differentiation and hyperplasia in female rats. Exp Biol Med. 2014;239(7):871–82.CrossRefGoogle Scholar
  54. Deas E, Wood NW, Plun-Favreau H. Mitophagy and Parkinson’s disease: the PINK1-parkin link. Biochim Biophys Acta. 2010;1813(4):623–33.PubMedCrossRefGoogle Scholar
  55. Deijen JB, de Boer H, van der Veen EA. Cognitive changes during growth hormone replacement in adult men. Psychoneuroendocrinology. 1998;23(1):45–55.PubMedCrossRefGoogle Scholar
  56. Dentremont KD, Ye P, D’Ercole AJ, O’Kusky JR. Increased insulin-like growth factor-I (IGF-I) expression during early postnatal development differentially increases neuron number and growth in medullary nuclei of the mouse. Brain Res Dev Brain Res. 1999;114(1):135–41.PubMedCrossRefGoogle Scholar
  57. DeWitt MR, Chen P, Aschner M. Manganese efflux in parkinsonism: insights from newly characterized SLC30A10 mutations. Biochem Biophys Res Commun. 2013;432(1):1–4.PubMedPubMedCentralCrossRefGoogle Scholar
  58. Dhamoon MS, Noble JM, Craft S. Intranasal insulin improves cognition and modulates -amyloid in early ad. Neurology. 2009;72(3):292–4.PubMedCrossRefGoogle Scholar
  59. Dieter HH, Bayer TA, Multhaup G. Environmental copper and manganese in the pathophysiology of neurologic diseases (Alzheimer’s disease and Manganism). Acta Hydrochim Hydrobiol. 2005;33(1):72–8.CrossRefGoogle Scholar
  60. Dormond O, Ponsonnet L, Hasmim M, Foletti A, Rüegg C. Manganese-induced integrin affinity maturation promotes recruitment of alpha V beta 3 integrin to focal adhesions in endothelial cells: evidence for a role of phosphatidylinositol 3-kinase and Src. Thromb Haemost. 2004;92(1):151–61.PubMedGoogle Scholar
  61. Duarte AI, Petit GH, Ranganathan S, Li JY, Oliveira CR, Brundin P, Björkqvist M, Rego AC. IGF-1 protects against diabetic features in an in vivo model of Huntington’s disease. Exp Neurol. 2011;231(2):314–9.PubMedCrossRefGoogle Scholar
  62. Ehlayel M, Soliman A, Sanctis V. Linear growth and endocrine function in children with ataxia telangiectasia. Ind J Endocrinol Metabol. 2014;18(7):93–6.CrossRefGoogle Scholar
  63. Ekmekcioglu C, Prohaska C, Pomazal K, Steffan I, Schernthaner G, Marktl W. Concentrations of seven trace elements in different hematological matrices in patients with type 2 diabetes as compared to healthy controls. Biol Trace Elem Res. 2001;79(3):205–19.PubMedCrossRefGoogle Scholar
  64. Exil V, Ping L, Yu Y, Chakraborty S, Caito SW, Wells KS, Karki P, Lee E, Aschner M. Activation of MAPK and FoxO by manganese (Mn) in rat neonatal primary astrocyte cultures. PLoS One. 2014;9(5)Google Scholar
  65. Farrer LA. Diabetes mellitus in Huntington disease. Clin Genet. 1985;27(1):62–7.PubMedCrossRefGoogle Scholar
  66. Fernandez AM, Torres-Alemán I. The many faces of insulin-like peptide signalling in the brain. Nat Rev Neurosci. 2012;13(4):225–39.PubMedCrossRefGoogle Scholar
  67. Ferrante RJ, Andreassen OA, Jenkins BG, Dedeoglu A, Kuemmerle S, Kubilus JK, Kaddurah-Daouk R, Hersch SM, Beal MF. Neuroprotective effects of creatine in a transgenic mouse model of Huntington’s disease. J Neurosci Off J Soc Neurosci. 2000;20(12):4389–97.Google Scholar
  68. Ferrante RJ, Andreassen OA, Dedeoglu A, Ferrante KL, Jenkins BG, Hersch SM, Beal FM. Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington’s disease. J Neurosci Off J Soc Neurosci. 2002;22(5):1592–9.Google Scholar
  69. Ferreira IL, Nascimento MV, Ribeiro M, Almeida S, Cardoso SM, Grazina M, Pratas J, Santos M, Januário C, Oliveira CR and Rego CA (2010). Mitochondrial-dependent apoptosis in Huntington’s disease human cybrids. Exp Neurol 222 (2): 243–255.Google Scholar
  70. Ferreira LI, Cunha-Oliveira T, Nascimento MV, Ribeiro M, Proença TM, Januário C, Oliveira CR, Rego CA. Bioenergetic dysfunction in Huntington’s disease human cybrids. Exp Neurol. 2011;231(1):127–34.PubMedCrossRefGoogle Scholar
  71. Filosto M, Scarpelli M, Cotelli M, Vielmi V, Todeschini A, Gregorelli V, Tonin P, Tomelleri G, Padovani A. The role of mitochondria in neurodegenerative diseases. J Neurol. 2011;258(10):1763–74.PubMedCrossRefGoogle Scholar
  72. Freude S, Schilbach K, Schubert M. The role of IGF-1 receptor and insulin receptor signaling for the pathogenesis of Alzheimer’s disease: from model organisms to human disease. Curr Alzheimer Res. 2009;6(3):213–23.PubMedCrossRefGoogle Scholar
  73. Gaba AM, Zhang K, Marder K, Moskowitz CB, Werner P, Boozer CN. Energy balance in early-stage Huntington disease. Am J Clin Nutr. 2005;81(6):1335–41.PubMedGoogle Scholar
  74. Gal J, Ström AL, Kwinter DM, Kilty R, Zhang J, Shi P, Fu W, Wooten MW, Zhu H. Sequestosome 1/p62 links familial ALS mutant SOD1 to LC3 via an ubiquitin-independent mechanism. J Neurochem. 2009;111(4):1062–73.PubMedPubMedCentralCrossRefGoogle Scholar
  75. Gasparini L, Xu H. Potential roles of insulin and IGF-1 in Alzheimer’s disease. Trends Neurosci. 2003;26(8):404–6.PubMedCrossRefGoogle Scholar
  76. Gauthier LR, Charrin BC, Borrell-Pagès M, Dompierre JP, Rangone H, Cordelières FP, Mey J, MacDonald ME, Leßmann V, Humbert S, Saudou F. Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell. 2004;118(1):127–38.PubMedCrossRefGoogle Scholar
  77. Geisler S, Holmström KM, Skujat D, Fiesel FC, Rothfuss OC, Kahle PJ, Springer W. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol. 2010;12(2):119–31.PubMedCrossRefGoogle Scholar
  78. Gelman A, Rawet-Slobodkin M, Elazar Z. Huntingtin facilitates selective autophagy. Nat Cell Biol. 2015;17(3):214–5.PubMedCrossRefGoogle Scholar
  79. Gines S, Ivanova E, Seong I-S, Saura CA, MacDonald ME. Enhanced Akt signaling is an early pro-survival response that reflects N-methyl-D-aspartate receptor activation in Huntington’s disease knock-in striatal cells. J Biol Chem. 2003;278(50):50514–22.PubMedCrossRefGoogle Scholar
  80. Godau J, Herfurth M, Kattner B, Gasser T, Berg D. Increased serum insulin-like growth factor 1 in early idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2010;81(5):536–8.PubMedCrossRefGoogle Scholar
  81. Goetz EM, Shankar B, Zou Y, Morales JC, Luo X, Araki S, Bachoo R, Mayo LD, Boothman DA. ATM-dependent IGF-1 induction regulates secretory clusterin expression after DNA damage and in genetic instability. Oncogene. 2011;30(35):3745–54.PubMedPubMedCentralCrossRefGoogle Scholar
  82. Gomes C, Escrevente C, Costa J. Mutant superoxide dismutase 1 overexpression in NSC-34 cells: effect of trehalose on aggregation, TDP-43 localization and levels of co-expressed glycoproteins. Neurosci Lett. 2010;475(3):145–9.PubMedCrossRefGoogle Scholar
  83. Gong L, Zhang QL, Zhang N, Hua WY, Huang YX, Di PW, Huang T, Xu XS, Liu CF, Hu LF, Luo WF. Neuroprotection by urate on 6-OHDA-lesioned rat model of Parkinson’s disease: linking to Akt/GSK3β signaling pathway. J Neurochem. 2012;123(5):876–85.PubMedCrossRefGoogle Scholar
  84. Goodman A, Murgatroyd PR, Medina-Gomez G, Wood NI, Finer N, Vidal-Puig AJ, Morton JA, Barker RA. The metabolic profile of early Huntington’s disease- a combined human and transgenic mouse study. Exp Neurol. 2008;210(2):691–8.PubMedCrossRefGoogle Scholar
  85. Gorojod RM, Alaimo A, Porte Alcon S, Pomilio C, Saravia F, Kotler ML. The autophagic- lysosomal pathway determines the fate of glial cells under manganese- induced oxidative stress conditions. Free Radic Biol Med. 2015;87:237–51.PubMedCrossRefGoogle Scholar
  86. Gouarné C, Tardif G, Tracz J, Latyszenok V, Michaud M, Clemens L, Yu-Taeger L, Nguyen H, Bordet T, Pruss RM. Early deficits in glycolysis are specific to striatal neurons from a rat model of Huntington disease. PLoS One. 2013;8(11)Google Scholar
  87. Greenwood BN, Fleshner M. Exercise, learned helplessness, and the stress-resistant brain. NeuroMolecular Med. 2008;10(2):81–98.PubMedCrossRefGoogle Scholar
  88. Griffin RJ, Moloney A, Kelliher M, Johnston JA, Ravid R, Dockery P, O’Connor R, O’Neill C. Activation of Akt/PKB, increased phosphorylation of Akt substrates and loss and altered distribution of Akt and PTEN are features of Alzheimer’s disease pathology. J Neurochem. 2005;93(1):105–17.PubMedCrossRefGoogle Scholar
  89. Guilarte TR. APLP1, Alzheimer’s-like pathology and neurodegeneration in the frontal cortex of manganese-exposed non-human primates. Neurotoxicology. 2010a;31(5):572–4.PubMedPubMedCentralCrossRefGoogle Scholar
  90. Guilarte TR. Manganese and Parkinson’s disease: a critical review and new findings. Environ Health Perspect. 2010b;118(8):1071–80.PubMedPubMedCentralCrossRefGoogle Scholar
  91. Guilarte TR, Gonzales KK. Manganese-induced parkinsonism is not idiopathic Parkinson’s disease: environmental and genetic evidence. Toxicol Sci. 2015;146(2):204–12.PubMedPubMedCentralCrossRefGoogle Scholar
  92. Gunter TE, Gavin CE, Gunter KK. The case for manganese interaction with mitochondria. Neurotoxicology. 2009;30(4):727–9.PubMedPubMedCentralCrossRefGoogle Scholar
  93. Gusella JF, MacDonald ME. Huntington’s disease: the case for genetic modifiers. Genome Med. 2009;1(8):80.PubMedPubMedCentralCrossRefGoogle Scholar
  94. Haj-ali V, Mohaddes G, Babri SH. Intracerebroventricular insulin improves spatial learning and memory in male Wistar rats. Behav Neurosci. 2009;123(6):1309.PubMedCrossRefGoogle Scholar
  95. Halaby M-J, Hibma JC, He J, Yang D-Q. ATM protein kinase mediates full activation of Akt and regulates glucose transporter 4 translocation by insulin in muscle cells. Cell Signal. 2008;20(8):1555–63.PubMedCrossRefGoogle Scholar
  96. Hare DJ, Faux NG, Roberts BR, Volitakis I, Martins RN, Bush AI. Lead and manganese levels in serum and erythrocytes in Alzheimer’s disease and mild cognitive impairment: results from the Australian imaging, biomarkers and lifestyle flagship study of ageing. Metallomics. 2016;8(6):628–32.PubMedCrossRefGoogle Scholar
  97. Harischandra DS, Jin H, Anantharam V, Kanthasamy A, Kanthasamy AG. α-Synuclein protects against manganese neurotoxic insult during the early stages of exposure in a dopaminergic cell model of Parkinson’s disease. Toxicol Sci. 2015;143(2):454–68.PubMedCrossRefGoogle Scholar
  98. Harris H, Rubinsztein DC. Control of autophagy as a therapy for neurodegenerative disease. Nat Rev Neurol. 2011;8(2):108–17.PubMedCrossRefGoogle Scholar
  99. Hiney JK, Srivastava VK, Dees WL. Manganese induces IGF-1 and cyclooxygenase-2 gene expressions in the basal hypothalamus during prepubertal female development. Toxicol Sci Off J Soc Toxicol. 2011;121(2):389–96.CrossRefGoogle Scholar
  100. Ho C-mJ, Zheng S, Comhair SA, Farver C, Erzurum SC. Differential expression of manganese superoxide dismutase and catalase in lung cancer. Cancer Res. 2001;61(23):8578–85.Google Scholar
  101. Hodge RD, D’Ercole JA, O’Kusky JR. Insulin-like growth factor-I accelerates the cell cycle by decreasing G1 phase length and increases cell cycle reentry in the embryonic cerebral cortex. J Neurosci Off J Soc Neurosci. 2004;24(45):10201–10.CrossRefGoogle Scholar
  102. Hölscher C. First clinical data of the neuroprotective effects of nasal insulin application in patients with Alzheimer’s disease. Alzheimer’s Dementia J Alzheimer’s Assoc. 2014;10(1 Suppl):7.Google Scholar
  103. Homolak J, Janeš I, Filipović M. The role of IGF-1 in neurodegenerative diseases. Gyrus. 2015;3(3):162–7.CrossRefGoogle Scholar
  104. Horning KJ, Caito SW, Tipps KG, Bowman AB, Aschner M. Manganese is essential for neuronal health. Annu Rev Nutr. 2015;35:71–108.PubMedCrossRefGoogle Scholar
  105. Hu Y, Rosen DG, Zhou Y, Feng L, Yang G, Liu J, Huang P. Mitochondrial manganese-superoxide dismutase expression in ovarian cancer: role in cell proliferation and response to oxidative stress. J Biol Chem. 2005;280(47):39485–92.PubMedCrossRefGoogle Scholar
  106. Humbert S, Saudou F. Huntingtin phosphorylation and signaling pathways that regulate toxicity in Huntington’s disease. Clin Neurosci Res. 2003;3(3):149–55.CrossRefGoogle Scholar
  107. Humbert S, Bryson EA, Cordelières FP, Connors NC, Datta SR, Finkbeiner S, Greenberg ME, Saudou F. The IGF-1/Akt pathway is neuroprotective in Huntington’s disease and involves huntingtin phosphorylation by Akt. Dev Cell. 2002;2(6):831–7.PubMedCrossRefGoogle Scholar
  108. Hurlbert MS, Zhou W, Wasmeier C, Kaddis FG, Hutton JC, Freed CR. Mice transgenic for an expanded CAG repeat in the Huntington’s disease gene develop diabetes. Diabetes. 1999;48(3):649–51.PubMedCrossRefGoogle Scholar
  109. Hurtado-Chong A, Yusta-Boyo MJ, Vergaño-Vera E, Bulfone A, Pablo F, Vicario-Abejón C. IGF-I promotes neuronal migration and positioning in the olfactory bulb and the exit of neuroblasts from the subventricular zone. Eur J Neurosci. 2009;30(5):742–55.PubMedCrossRefGoogle Scholar
  110. Ismailoglu I, Chen Q, Popowski M, Yang L, Gross SS, Brivanlou AH. Huntingtin protein is essential for mitochondrial metabolism, bioenergetics and structure in murine embryonic stem cells. Dev Biol. 2014;391(2):230–40.PubMedPubMedCentralCrossRefGoogle Scholar
  111. Jang B-CC. Induction of COX-2 in human airway cells by manganese: role of PI3K/PKB, p38 MAPK, PKCs, Src, and glutathione depletion. Toxicology in vitro : an international journal published in association with BIBRA. 2009;23(1):120–6.CrossRefGoogle Scholar
  112. Jiu Y-M, Yue Y, Yang S, Liu L, Yu J-W, Wu Z-X, Xu T. Insulin-like signaling pathway functions in integrative response to an olfactory and a gustatory stimuli in Caenorhabditis elegans. Protein Cell. 2010;1(1):75–81.PubMedPubMedCentralCrossRefGoogle Scholar
  113. Johansson P, Åberg D, Johansson J-O, Mattsson N, Hansson O, Ahrén B, Isgaard J, Åberg DN, Blennow K, Zetterberg H, Wallin A, Svensson J. Serum but not cerebrospinal fluid levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) are increased in Alzheimer’s disease. Psychoneuroendocrinology. 2013;38(9):1729–37.PubMedCrossRefGoogle Scholar
  114. Johri A, Beal FM. Mitochondrial dysfunction in neurodegenerative diseases. J Pharmacol Exp Ther. 2012;342(3):619–30.PubMedPubMedCentralCrossRefGoogle Scholar
  115. Josefsen K, Nielsen MD, Jørgensen KH, Bock T, Nørremølle A, Sørensen SA, Naver B, Hasholt L. Impaired glucose tolerance in the R6/1 transgenic mouse model of Huntington’s disease. J Neuroendocrinol. 2007;20(2):165–72.PubMedCrossRefGoogle Scholar
  116. Kalia K, Jiang W, Zheng W. Manganese accumulates primarily in nuclei of cultured brain cells. Neurotoxicology. 2008;29(3):466–70.PubMedPubMedCentralCrossRefGoogle Scholar
  117. Kanyo ZF, Scolnick LR, Ash DE, Christianson DW. Structure of a unique binuclear manganese cluster in arginase. Nature. 1996;383(6600):554–7.PubMedCrossRefGoogle Scholar
  118. Keen CL, Baly DL, Lönnerdal B. Metabolic effects of high doses of manganese in rats. Biol Trace Elem Res. 1984;6(4):309–15.PubMedCrossRefGoogle Scholar
  119. Kieslich M, Hoche F, Reichenbach J, Weidauer S, Porto L, Vlaho S, Schubert R, Zielen S. Extracerebellar MRI—lesions in ataxia telangiectasia go along with deficiency of the GH/IGF-1 Axis, markedly reduced body weight, high ataxia scores and advanced age. Cerebellum. 2010;9(2):190–7.PubMedCrossRefGoogle Scholar
  120. Kim J, Moody JP, Edgerly CK, Bordiuk OL, Cormier K, Smith K, Beal FM, Ferrante RJ. Mitochondrial loss, dysfunction and altered dynamics in Huntington's disease. Hum Mol Genet. 2010;19(20):3919–35.PubMedPubMedCentralCrossRefGoogle Scholar
  121. Koh ES, Kim SJ, Yoon HE, Chung JH, Chung S, Park CW, Chang YS, Shin SJ. Association of blood manganese level with diabetes and renal dysfunction: a cross-sectional study of the Korean general population. BMC Endocrine Disorders. 2014;14:24.PubMedPubMedCentralCrossRefGoogle Scholar
  122. Koroshetz WJ, Jenkins BG, Rosen BR, Beal FM. Energy metabolism defects in Huntington’s disease and effects of coenzyme Q10. Ann Neurol. 1997;41(2):160–5.PubMedCrossRefGoogle Scholar
  123. Krishnamurthi R, Stott S, Maingay M, Faull RLM, McCarthy D, Gluckman P, Guan J. N-terminal tripeptide of IGF-1 improves functional deficits after 6-OHDA lesion in rats. Neuroreport. 2004;15(10):1601–4.PubMedCrossRefGoogle Scholar
  124. Kumar A, Singh S, Kumar V, Kumar D, Agarwal S, Rana M. Huntington’s disease: an update of therapeutic strategies. Gene. 2015;556(2):91–7.PubMedCrossRefGoogle Scholar
  125. Kwakye GF, Li D, Bowman AB. Novel high-throughput assay to assess cellular manganese levels in a striatal cell line model of Huntington’s disease confirms a deficit in manganese accumulation. Neurotoxicology. 2011;32(5):630–9.PubMedPubMedCentralCrossRefGoogle Scholar
  126. Kwakye GF, Paoliello MM, Mukhopadhyay S, Bowman AB, Aschner M. Manganese-induced parkinsonism and Parkinson’s disease: shared and distinguishable features. Int J Environ Res Public Health. 2015;12(7):7519–40.PubMedPubMedCentralCrossRefGoogle Scholar
  127. Lalić NM, Marić J, Svetel M, Jotić A, Stefanova E, Lalić K, Dragašević N, Miličić T, Lukić L, Kostić VS. Glucose homeostasis in Huntington disease: abnormalities in insulin sensitivity and early-phase insulin secretion. Arch Neurol. 2008;65(4):476–80.PubMedCrossRefGoogle Scholar
  128. Landles C, Bates GP. Huntingtin and the molecular pathogenesis of Huntington’s disease. EMBO Rep. 2004;5(10):958–63.PubMedPubMedCentralCrossRefGoogle Scholar
  129. Larsen NA, Pakkenberg H, Damsgaard E, Heydorn K. Topographical distribution of arsenic, manganese, and selenium in the normal human brain. J Neurol Sci. 1979;42(3):407–16.PubMedCrossRefGoogle Scholar
  130. Lee B, Pine M, Johnson L, Rettori V, Hiney JK, Dees LW. Manganese acts centrally to activate reproductive hormone secretion and pubertal development in male rats. Reproductive toxicology (Elmsford, NY). 2006;22(4):580–5.CrossRefGoogle Scholar
  131. Lee B, Hiney JK, Pine MD, Srivastava VK, Dees LW. Manganese stimulates luteinizing hormone releasing hormone secretion in prepubertal female rats: hypothalamic site and mechanism of action. J Physiol. 2007;578(3):765–72.PubMedCrossRefGoogle Scholar
  132. Lee S-H, Jouihan HA, Cooksey RC, Jones D, Kim HJ, Winge DR, McClain DA. Manganese supplementation protects against diet-induced diabetes in wild type mice by enhancing insulin secretion. Endocrinology. 2013;154(3):1029–38.PubMedPubMedCentralCrossRefGoogle Scholar
  133. Lee JH, Tecedor L, Chen Y, Monteys A, Sowada MJ, Thompson LM, Davidson BL. Reinstating aberrant mTORC1 activity in Huntington’s disease mice improves disease phenotypes. Neuron. 2014;85(2):303–15.PubMedPubMedCentralCrossRefGoogle Scholar
  134. Leyva-Illades D, Chen P, Zogzas CE, Hutchens S, Mercado JM, Swaim CD, Morrisett RA, Bowman AB, Aschner M, Mukhopadhyay S. SLC30A10 is a cell surface-localized manganese efflux transporter, and parkinsonism-causing mutations block its intracellular trafficking and efflux activity. J Neurosci. 2014;34(42):14079–95.PubMedPubMedCentralCrossRefGoogle Scholar
  135. Lim J, Yue Z. Neuronal aggregates: formation, clearance, and spreading. Dev Cell. 2015;32(4):491–501.PubMedPubMedCentralCrossRefGoogle Scholar
  136. Liou J-C, Tsai F-Z, Ho S-Y. Potentiation of quantal secretion by insulin-like growth factor-1 at developing motoneurons in Xenopus cell culture. J Physiol. 2003;553(Pt 3):719–28.PubMedPubMedCentralCrossRefGoogle Scholar
  137. Liu W, Ye P, O’Kusky JR, D’Ercole JA. Type 1 insulin-like growth factor receptor signaling is essential for the development of the hippocampal formation and dentate gyrus. J Neurosci Res. 2009;87(13):2821–32.PubMedCrossRefGoogle Scholar
  138. Liu Y, Liu F, Grundke-Iqbal I, Iqbal K, Gong CX. Deficient brain insulin signalling pathway in Alzheimer’s disease and diabetes. J Pathol. 2011;225(1):54–62.PubMedPubMedCentralCrossRefGoogle Scholar
  139. Lopes C, Ribeiro M, Duarte AI, Humbert S, Saudou F, Pereira de Almeida L, Hayden M, Rego AC. IGF-1 intranasal administration rescues Huntington’s disease phenotypes in YAC128 mice. Mol Neurobiol. 2014;49(3):1126–42.PubMedCrossRefGoogle Scholar
  140. Lou S, Lepak T, Eberly LE, Roth B, Cui W, Zhu X-H, Öz G, Dubinsky JM. Oxygen consumption deficit in Huntington disease mouse brain under metabolic stress. Human Mol Genet. 2016;Google Scholar
  141. Luo X, Suzuki M, Ghandhi SA, Amundson SA, Boothman DA. ATM regulates insulin-like growth factor 1-secretory Clusterin (IGF-1-sCLU) expression that protects cells against senescence. PLoS One. 2014;9(6)Google Scholar
  142. Ma J, Jiang Q, Xu J, Sun Q, Qiao Y, Chen W, Wu Y, Wang Y, Xiao Q, Liu J, Tang H, Chen S. Plasma insulin-like growth factor 1 is associated with cognitive impairment in Parkinson’s disease. Dement Geriatr Cogn Disord. 2015;39(5–6):251–6.PubMedCrossRefGoogle Scholar
  143. Marks DR, Tucker K, Cavallin MA, Mast TG, Fadool DA. Awake intranasal insulin delivery modifies protein complexes and alters memory, anxiety, and olfactory behaviors. J Neurosci. 2009;29(20):6734–51.PubMedPubMedCentralCrossRefGoogle Scholar
  144. Martin LJ. Chapter 11 biology of mitochondria in neurodegenerative diseases. Prog Mol Biol Transl Sci. 2012;107:355–415.PubMedPubMedCentralCrossRefGoogle Scholar
  145. Martin WWR, Wieler M, Hanstock CC. Is brain lactate increased in Huntington’s disease? J Neurol Sci. 2007;263(1–2):70–4.PubMedCrossRefGoogle Scholar
  146. Martin DDO, Ladha S, Ehrnhoefer DE, Hayden MR. Autophagy in Huntington disease and huntingtin in autophagy. Trends Neurosci. 2014;38(1):26–35.PubMedCrossRefGoogle Scholar
  147. Martinez-Vicente M, Talloczy Z, Wong E, Tang G, Koga H, Kaushik S, de Vries R, Arias E, Harris S, Sulzer D, Cuervo A. Cargo recognition failure is responsible for inefficient autophagy in Huntington’s disease. Nat Neurosci. 2010;13(5):567–76.PubMedPubMedCentralCrossRefGoogle Scholar
  148. Maydan M, McDonald PC, Sanghera J, Yan J, Rallis C, Pinchin S, Hannigan GE, Foster LJ, Ish-Horowicz D, Walsh MP, Dedhar S. Integrin-linked kinase is a functional Mn2+−dependent protein kinase that regulates glycogen synthase kinase-3β (GSK-3β) phosphorylation. PLoS One. 2010;5(8)Google Scholar
  149. Metzler M, Gan L, Mazarei G, Graham RK, Liu L, Bissada N, Lu G, Leavitt BR, Hayden MR. Phosphorylation of huntingtin at Ser421 in YAC128 neurons is associated with protection of YAC128 neurons from NMDA-mediated excitotoxicity and is modulated by PP1 and PP2A. J Neurosci. 2010;30(43):14318–29.PubMedCrossRefGoogle Scholar
  150. Michiorri S, Gelmetti V, Giarda E, Lombardi F, Romano F, Marongiu R, Nerini-Molteni S, Sale P, Vago R, Arena G, Torosantucci L, Cassina L, Russo MA, Dallapiccola B, Valente EM, Casari G. The Parkinson-associated protein PINK1 interacts with Beclin1 and promotes autophagy. Cell Death Differ. 2010;17(6):962–74.PubMedCrossRefGoogle Scholar
  151. Milakovic T, Johnson GVW. Mitochondrial respiration and ATP production are significantly impaired in striatal cells expressing mutant huntingtin. J Biol Chem. 2005;280(35):30773–82.PubMedCrossRefGoogle Scholar
  152. Miles PD, Treuner K, Latronica M, Olefsky JM, Barlow C. Impaired insulin secretion in a mouse model of ataxia telangiectasia. Am J Physiol Endocrinol Metab. 2007;293(1):4.CrossRefGoogle Scholar
  153. Miyata S, Nakamura S, Nagata H, Kameyama M. Increased manganese level in spinal cords of amyotrophic lateral sclerosis determined by radiochemical neutron activation analysis. J Neurol Sci. 1983;61(2):283–93.PubMedCrossRefGoogle Scholar
  154. Mochel F, Charles P, Seguin F, Barritault J, Coussieu C, Perin L, Bouc Y, Gervais C, Carcelain G, Vassault A, Feingold J, Rabier D, Durr A. Early energy deficit in Huntington disease: identification of a plasma biomarker traceable during disease progression. PLoS One. 2007;2(7)Google Scholar
  155. Moloney AM, Griffin RJ, Timmons S, O’Connor R, Ravid R, O’Neill C. Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signalling. Neurobiol Aging. 2010;31Google Scholar
  156. de la Monte SM, Wands JR. Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimer’s disease. J Alzheimers Dis. 2005;7Google Scholar
  157. Morello M, Canini A, Mattioli P, Sorge RP, Alimonti A, Bocca B, Forte G, Martorana A, Bernardi G, Sancesario G. Sub-cellular localization of manganese in the basal ganglia of normal and manganese-treated rats an electron spectroscopy imaging and electron energy-loss spectroscopy study. Neurotoxicology. 2008;29(1):60–72.PubMedCrossRefGoogle Scholar
  158. Morrison BD, Feltz SM, Pessin JE. Polylysine specifically activates the insulin-dependent insulin receptor protein kinase. J Biol Chem. 1989;264(17):9994–10001.PubMedGoogle Scholar
  159. Nagano I, Ilieva H, Shiote M, Murakami T, Yokoyama M, Shoji M, Abe K. Therapeutic benefit of intrathecal injection of insulin-like growth factor-1 in a mouse model of amyotrophic lateral sclerosis. J Neurol Sci. 2005;235Google Scholar
  160. Nagano I, Shiote M, Murakami T, Kamada H, Hamakawa Y, Matsubara E, Yokoyama M, Morita K, Shoji M, Abe K. Beneficial effects of intrathecal IGF-1 administration in patients with amyotrophic lateral sclerosis. Neurol Res. 2013;27(7):768–72.CrossRefGoogle Scholar
  161. Nagata H, Miyata S, Nakamura S, Kameyama M, Katsui Y. Heavy metal concentrations in blood cells in patients with amyotrophic lateral sclerosis. J Neurol Sci. 1985;67(2):173–8.PubMedCrossRefGoogle Scholar
  162. Naia L, Ferreira IL, Cunha-Oliveira T, Duarte AI, Ribeiro M, Rosenstock TR, Laço MNN, Ribeiro MJ, Oliveira CR, Saudou F, Humbert S, Rego AC. Activation of IGF-1 and insulin signaling pathways ameliorate mitochondrial function and energy metabolism in Huntington’s disease human lymphoblasts. Mol Neurobiol. 2015;51(1):331–48.PubMedCrossRefGoogle Scholar
  163. Naia L, Ribeiro M, Rodrigues J, Duarte AI, Lopes C, Rosenstock TR, Hayden MR and Rego CA (2016). Insulin and IGF-1 regularize energy metabolites in neural cells expressing full-length mutant huntingtin. Neuropeptides.Google Scholar
  164. Nakaso K, Ito S, Nakashima K. Caffeine activates the PI3K/Akt pathway and prevents apoptotic cell death in a Parkinson’s disease model of SH-SY5Y cells. Neurosci Lett. 2008;432Google Scholar
  165. Narendra D, Tanaka A, Suen D-F, Youle RJ. Parkin-induced mitophagy in the pathogenesis of Parkinson disease. Autophagy. 2009;5(5):706–8.PubMedCrossRefGoogle Scholar
  166. Neill C. PI3-kinase/Akt/mTOR signaling: impaired on/off switches in aging, cognitive decline and Alzheimer’s disease. Exp Gerontol. 2013;48(7):647–53.CrossRefGoogle Scholar
  167. Neulen A, Blaudeck N, Zittrich S, Metzler D, Pfitzer G, Stehle R. Mn2+−dependent protein phosphatase 1 enhances protein kinase A-induced Ca2+ desensitisation in skinned murine myocardium. Cardiovasc Res. 2007;74(1):124–32.PubMedCrossRefGoogle Scholar
  168. Nissenkorn A, Levy-Shraga Y, Banet-Levi Y, Lahad A, Sarouk I, Modan-Moses D. Endocrine abnormalities in ataxia telangiectasia: findings from a national cohort. Pediatr Res. 2016;79(6):889–94.PubMedCrossRefGoogle Scholar
  169. O’Kusky JR, Ye P, D’Ercole AJ. Insulin-like growth factor-I promotes neurogenesis and synaptogenesis in the hippocampal dentate gyrus during postnatal development. J Neurosci Off J Soc Neurosci. 2000;20(22):8435–42.Google Scholar
  170. Ochaba J, Lukacsovich T, Csikos G, Zheng S, Margulis J, Salazar L, Mao K, Lau AL, Yeung SY, Humbert S, Saudou F, Klionsky DJ, Finkbeiner S, Zeitlin SO, Marsh LJ, Housman DE, Thompson LM, Steffan JS. Potential function for the huntingtin protein as a scaffold for selective autophagy. Proc Natl Acad Sci. 2014;111(47):16889–94.PubMedPubMedCentralCrossRefGoogle Scholar
  171. Offen D, Shtaif B, Hadad D, Weizman A, Melamed E, Gil-Ad I. Protective effect of insulin-like-growth-factor-1 against dopamine-induced neurotoxicity in human and rodent neuronal cultures: possible implications for Parkinson’s disease. Neurosci Lett. 2001;316(3):129–32.PubMedCrossRefGoogle Scholar
  172. Oishi K, Watatani K, Itoh Y, Okano H, Guillemot F, Nakajima K, Gotoh Y. Selective induction of neocortical GABAergic neurons by the PDK1-Akt pathway through activation of Mash1. Proc Natl Acad Sci. 2009;106(31):13064–9.PubMedPubMedCentralCrossRefGoogle Scholar
  173. Oláh J, Klivényi P, Gardián G, Vécsei L, Orosz F, Kovacs GG, Westerhoff HV, Ovádi J. Increased glucose metabolism and ATP level in brain tissue of Huntington’s disease transgenic mice. FEBS J. 2008;275(19):4740–55.PubMedCrossRefGoogle Scholar
  174. Ozdinler HP, Macklis JD. IGF-I specifically enhances axon outgrowth of corticospinal motor neurons. Nat Neurosci. 2006;9(11):1371–81.PubMedCrossRefGoogle Scholar
  175. Paull TT, Gellert M. The 3′ to 5′ exonuclease activity of Mre 11 facilitates repair of DNA double-strand breaks. Mol Cell. 1998;1(7):969–79.PubMedCrossRefGoogle Scholar
  176. Peres T, Parmalee NL, Martinez-Finley EJ, Aschner M. Untangling the manganese-α-Synuclein web. Front Neurosci. 2016;10:364.PubMedPubMedCentralCrossRefGoogle Scholar
  177. Peretz S, Jensen R, Baserga R, Glazer PM. ATM-dependent expression of the insulin-like growth factor-I receptor in a pathway regulating radiation response. Proc Natl Acad Sci. 2001;98(4):1676–81.PubMedPubMedCentralCrossRefGoogle Scholar
  178. Peters TL, Beard JD, Umbach DM, Allen K, Keller J, Mariosa D, Sandler DP, Schmidt S, Fang F, Ye W, Kamel F. Blood levels of trace metals and amyotrophic lateral sclerosis. Neurotoxicology. 2016;54:119–26.PubMedPubMedCentralCrossRefGoogle Scholar
  179. Picillo M, Erro R, Santangelo G, Pivonello R, Longo K, Pivonello C, Vitale C, Amboni M, Moccia M, Colao A, Barone P, Pellecchia M. Insulin-like growth factor-1 and progression of motor symptoms in early, drug-naïve Parkinson’s disease. J Neurol. 2013;260(7):1724–30.PubMedCrossRefGoogle Scholar
  180. Podolsky S, Leopold N, Sax D. Increased frequency of diabetes mellitus in patients with Huntington’s chorea. Lancet. 1972;299(7765):1356–9.CrossRefGoogle Scholar
  181. Pouladi MA, Xie Y, Skotte NH, Ehrnhoefer DE, Graham RK, Kim JE, Bissada N, Yang XW, Paganetti P, Friedlander RM, Leavitt BR, Hayden MR. Full-length huntingtin levels modulate body weight by influencing insulin-like growth factor 1 expression. Hum Mol Genet. 2010;19(8):1528–38.PubMedPubMedCentralCrossRefGoogle Scholar
  182. Prohaska JR. Functions of trace elements in brain metabolism. Physiol Rev. 1987;67(3):858–901.PubMedGoogle Scholar
  183. Pryor WM, Biagioli M, Shahani N, Swarnkar S, Huang W-C, Page DT, MacDonald ME, Subramaniam S. Huntingtin promotes mTORC1 signaling in the pathogenesis of Huntington’s disease. Sci Signal. 2014;7(349)Google Scholar
  184. Quadri M, Federico A, Zhao T, Breedveld GJ, Battisti C, Delnooz C, Severijnen L-A, Di Toro ML, Mignarri A, Monti L, Sanna A, Lu P, Punzo F, Cossu G, Willemsen R, Rasi F, Oostra BA, van de Warrenburg BP, Bonifati V. Mutations in SLC30A10 cause parkinsonism and dystonia with Hypermanganesemia, polycythemia, and chronic liver disease. Am J Hum Genet. 2012;90(3):467–77.PubMedPubMedCentralCrossRefGoogle Scholar
  185. Quesada A, Lee BY, Micevych PE. PI3 kinase/Akt activation mediates estrogen and IGF-1 nigral DA neuronal neuroprotection against a unilateral rat model of Parkinson’s disease. Dev Neurobiol. 2008;68(5):632–44.PubMedPubMedCentralCrossRefGoogle Scholar
  186. Rauskolb S, Dombert B, Sendtner M. Insulin-like growth factor 1 in diabetic neuropathy and amyotrophic lateral sclerosis. Neurobiol Dis. 2016;Google Scholar
  187. Ravikumar B, Rubinsztein DC. Role of autophagy in the clearance of mutant huntingtin: a step towards therapy? Mol Asp Med. 2006;27(5–6):520–7.CrossRefGoogle Scholar
  188. Reddy HP, Mao P, Manczak M. Mitochondrial structural and functional dynamics in Huntington’s disease. Brain Res Rev. 2009;61(1):33–48.PubMedPubMedCentralCrossRefGoogle Scholar
  189. Reger MA, Watson GS, Green PS, Wilkinson CW, Baker LD, Cholerton B, Fishel MA, Plymate SR, Breitner JCS, DeGroodt W, Mehta P, Craft S. Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology. 2007;70(6):440–8.PubMedCrossRefGoogle Scholar
  190. Reyes ET, Perurena OH, Festoff BW, Jorgensen R, Moore WV. Insulin resistance in amyotrophic lateral sclerosis. J Neurol Sci. 1984;63(3):317–24.PubMedCrossRefGoogle Scholar
  191. Ribeiro M, Rosenstock TR, Oliveira AM, Oliveira CR, Rego AC. Insulin and IGF-1 improve mitochondrial function in a PI-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington’s disease knock-in striatal cells. Free Radic Biol Med. 2014;74:129–44.PubMedCrossRefGoogle Scholar
  192. Rickle A, Bogdanovic N, Volkman I, Winblad B, Ravid R, Cowburn RF. Akt activity in Alzheimer’s disease and other neurodegenerative disorders. Neuroreport. 2004;15(6):955–9.PubMedCrossRefGoogle Scholar
  193. Rivera EJ, Goldin A, Fulmer N, Tavares R, Wands JR, de la Monte SM. Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer’s disease: link to brain reductions in acetylcholine. J Alzheimers Dis. 2005;8Google Scholar
  194. Roos PM, Lierhagen S, Flaten T, Syversen T, Vesterberg O, Nordberg M. Manganese in cerebrospinal fluid and blood plasma of patients with amyotrophic lateral sclerosis. Exp Biol Med. 2012;237(7):803–10.CrossRefGoogle Scholar
  195. Root CM, Ko KI, Jafari A, Wang JW. Presynaptic facilitation by neuropeptide signaling mediates odor-driven food search. Cell. 2011;145(1):133–44.PubMedPubMedCentralCrossRefGoogle Scholar
  196. Rubenstein AH, Levin NW, Elliott GA. Manganese-induced hypoglycaemia. Lancet (London, England). 1962;2(7270):1348–51.CrossRefGoogle Scholar
  197. Rui Y-NN XZ, Patel B, Chen Z, Chen D, Tito A, David G, Sun Y, Stimming EF, Bellen HJ, Cuervo AM, Zhang S. Huntingtin functions as a scaffold for selective macroautophagy. Nat Cell Biol. 2015;17(3)Google Scholar
  198. Saavedra A, García-Martínez JM, Xifró X, Giralt A, Torres-Peraza JF, Canals JM, Díaz-Hernández M, Lucas JJ, Alberch J, Pérez-Navarro E. PH domain leucine-rich repeat protein phosphatase 1 contributes to maintain the activation of the PI3K/Akt pro-survival pathway in Huntington’s disease striatum. Cell Death Differ. 2009;17(2):324–35.PubMedCrossRefGoogle Scholar
  199. Saccà F, Quarantelli M, Rinaldi C, Tucci T, Piro R, Perrotta G, Carotenuto B, Marsili A, Palma V, Michele G, Brunetti A, Morra V, Filla A, Salvatore M. A randomized controlled clinical trial of growth hormone in amyotrophic lateral sclerosis: clinical, neuroimaging, and hormonal results. J Neurol. 2012;259(1):132–8.PubMedCrossRefGoogle Scholar
  200. Saleh N, Moutereau S, Durr A, Krystkowiak P, Azulay J-P, Tranchant C, Broussolle E, Morin F, Bachoud-Lévi A-C, Maison P. Neuroendocrine disturbances in Huntington’s disease. PLoS One. 2009;4(3)Google Scholar
  201. Saleh N, Moutereau S, Azulay JP, Verny C, Simonin C, Tranchant C, Hawajri EN, Bachoud-Lévi AC, Maison P, Group H. High insulinlike growth factor I is associated with cognitive decline in Huntington disease. Neurology. 2010;75(1):57–63.PubMedCrossRefGoogle Scholar
  202. Sarkar S, Rubinsztein DC. Huntington’s disease: degradation of mutant huntingtin by autophagy. FEBS J. 2008;275(17):4263–70.PubMedCrossRefGoogle Scholar
  203. Sarkar S, Ravikumar B, Floto RA, Rubinsztein DC. Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies. Cell Death Differ. 2008;16(1):46–56.PubMedCrossRefGoogle Scholar
  204. Sasazawa Y, Sato N, Umezawa K, Simizu S. Conophylline protects cells in cellular models of neurodegenerative diseases by inducing mammalian target of rapamycin (mTOR)-independent autophagy. J Biol Chem. 2015;290(10):6168–78.PubMedPubMedCentralCrossRefGoogle Scholar
  205. Sato T, Nakashima A, Guo L, Tamanoi F. Specific activation of mTORC1 by Rheb G-protein in vitro involves enhanced recruitment of its substrate protein. J Biol Chem. 2009;284(19):12783–91.PubMedPubMedCentralCrossRefGoogle Scholar
  206. Saudou F, Humbert S. The biology of huntingtin. Neuron. 2016;89(5):910–26.PubMedCrossRefGoogle Scholar
  207. Schilling G, Coonfield ML, Ross CA, Borchelt DR. Coenzyme Q10 and remacemide hydrochloride ameliorate motor deficits in a Huntington’s disease transgenic mouse model. Neurosci Lett. 2001;315(3):149–53.PubMedCrossRefGoogle Scholar
  208. Schubert M, Gautam D, Surjo D, Ueki K, Baudler S, Schubert D, Kondo T, Alber J, Galldiks N, Küstermann E. Role for neuronal insulin resistance in neurodegenerative diseases. Proc Nat Acad Sci USA. 2004:101.Google Scholar
  209. Schubert R, Reichenbach J, Zielen S. Growth factor deficiency in patients with ataxia telangiectasia. Clinical & Experimental Immunology. 2005;140(3):517–9.CrossRefGoogle Scholar
  210. Shahrabani-Gargir L, Pandita TK, Werner H. Ataxia-telangiectasia mutated gene controls insulin-like growth factor I receptor gene expression in a deoxyribonucleic acid damage response pathway via mechanisms involving zinc-finger transcription factors Sp1 and WT1. Endocrinology. 2004;145(12):5679–87.PubMedCrossRefGoogle Scholar
  211. Shen F, Cai W-S, Li J-L, Feng Z, Cao J, Xu B. The association between deficient manganese levels and breast cancer: a meta-analysis. Int J Clin Exp Med. 2015;8(3):3671–80.PubMedPubMedCentralGoogle Scholar
  212. Skeberdis VA, Lan J, Zheng X, Zukin RS, Bennett MV. Insulin promotes rapid delivery of N-methyl-D- aspartate receptors to the cell surface by exocytosis. Proc Natl Acad Sci U S A. 2001;98(6):3561–6.PubMedPubMedCentralCrossRefGoogle Scholar
  213. Sørensen AS, Fenger K, Olsen JH. Significantly lower incidence of cancer among patients with Huntington disease. Cancer. 1999;86(7):1342–6.PubMedCrossRefGoogle Scholar
  214. Sorenson EJ, Windbank AJ, Mandrekar JN, Bamlet WR, Appel SH, Armon C, Barkhaus PE, Bosch P, Boylan K, David WS, Feldman E, Glass J, Gutmann L, Katz J, King W, Luciano CA, McCluskey LF, Nash S, Newman DS, Pascuzzi RM, Pioro E, Sams LJ, Scelsa S, Simpson EP, Subramony SH, Tiryaki E, Thornton CA. Subcutaneous IGF-1 is not beneficial in 2-year ALS trial. Neurology. 2008;71(22):1770–5.PubMedPubMedCentralCrossRefGoogle Scholar
  215. Sosa L, Dupraz S, Laurino L, Bollati F, Bisbal M, Cáceres A, Pfenninger KH, Quiroga S. IGF-1 receptor is essential for the establishment of hippocampal neuronal polarity. Nat Neurosci. 2006;9(8):993–5.PubMedCrossRefGoogle Scholar
  216. Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Bredesen D, Richardson A, Strong R, Galvan V. Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-β levels in a mouse model of Alzheimer’s disease. PLoS One. 2010;5(4)Google Scholar
  217. Srivastava VK, Hiney JK, Dees LW. Prepubertal ethanol exposure alters hypothalamic transforming growth factor-α and erbB1 receptor signaling in the female rat. Alcohol. 2011;45(2):173–81.PubMedCrossRefGoogle Scholar
  218. Srivastava VK, Hiney JK, Dees WL. Early life manganese exposure upregulates tumor-associated genes in the hypothalamus of female rats: relationship to manganese-induced precocious puberty. Toxicol Sci. 2013;136(2):373–81.PubMedPubMedCentralCrossRefGoogle Scholar
  219. Srivastava VK, Hiney JK, Dees WL. Manganese stimulated Kisspeptin is mediated by the insulin-like growth factor-1/Akt/ mammalian target of rapamycin pathway in the prepubertal female rat. Endocrinology. 2016;Google Scholar
  220. Stansfield KH, Bichell T, Bowman AB, Guilarte TR. BDNF and huntingtin protein modifications by manganese: implications for striatal medium spiny neuron pathology in manganese neurotoxicity. J Neurochem. 2014;131(5):655–66.PubMedPubMedCentralCrossRefGoogle Scholar
  221. Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu JX, Wands JR, de la Monte SM. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease–is this type 3 diabetes? J Alzheimer’s Dis. 2005;7Google Scholar
  222. Subasinghe S, Greenbaum AL, McLean P. The insulin-mimetic action of Mn2+: involvement of cyclic nucleotides and insulin in the regulation of hepatic hexokinase and glucokinase. Biochem Med. 1985;34(1):83–92.PubMedCrossRefGoogle Scholar
  223. Sulzer D. Multiple hit hypotheses for dopamine neuron loss in Parkinson’s disease. Trends Neurosci. 2007;30(5):244–50.PubMedCrossRefGoogle Scholar
  224. Suzanne M, Wands JR. Alzheimer’s disease is type 3 diabetes—evidence reviewed. J Diabetes Sci Technol. 2008;2Google Scholar
  225. Tabrizi SJ, Blamire AM, Manners DN, Rajagopalan B, Styles P, Schapira AHV, Warner TT. Creatine therapy for Huntington’s disease: clinical and MRS findings in a 1-year pilot study. Neurology. 2003;61(1):141–2.PubMedCrossRefGoogle Scholar
  226. Takeda A. Manganese action in brain function. Brain Res Rev. 2003;41(1):79–87.PubMedCrossRefGoogle Scholar
  227. Tidball AM, Bryan MR, Uhouse MA, Kumar KK, Aboud AA, Feist JE, Ess KC, Neely DM, Aschner M, Bowman AB. A novel manganese-dependent ATM-p53 signaling pathway is selectively impaired in patient-based neuroprogenitor and murine striatal models of Huntington’s disease. Hum Mol Genet. 2015a;24(7):1929–44.PubMedCrossRefGoogle Scholar
  228. Tidball AM, Bichell T, Bowman AB. Manganese in health and disease. rsc. 2015b:540–73.Google Scholar
  229. Timmons S, Coakley MF, Moloney AM, Neill C. Akt signal transduction dysfunction in Parkinson’s disease. Neurosci Lett. 2009;467(1):30–5.PubMedCrossRefGoogle Scholar
  230. Tong M, Dong M, de la Monte SM. Brain insulin-like growth factor and neurotrophin resistance in Parkinson’s disease and dementia with Lewy bodies: potential role of manganese neurotoxicity. J Alzheimer’s Dis JAD. 2009;16(3):585–99.PubMedCrossRefGoogle Scholar
  231. Torres-Aleman I. Targeting insulin-like growth factor-1 to treat Alzheimer’s disease. Expert Opin Ther Targets. 2007;11(12):1535–42.PubMedCrossRefGoogle Scholar
  232. Trejo JL, Llorens-Martín MV, Torres-Alemán I. The effects of exercise on spatial learning and anxiety-like behavior are mediated by an IGF-I-dependent mechanism related to hippocampal neurogenesis. Mol Cell Neurosci. 2007;37(2):402–11.PubMedCrossRefGoogle Scholar
  233. Truant R, Atwal R, Desmond C, Munsie L, Tran T. Huntington’s disease: revisiting the aggregation hypothesis in polyglutamine neurodegenerative diseases. FEBS J. 2008;275(17):4252–62.PubMedCrossRefGoogle Scholar
  234. Trujillo KM, Yuan SS, Lee EY, Sung P. Nuclease activities in a complex of human recombination and DNA repair factors Rad50, Mre11, and p95. J Biol Chem. 1998;273(34):21447–50.PubMedCrossRefGoogle Scholar
  235. Valenciano A, Henríquez-Hernández L, Moreno M, Lloret M, Lara P. Role of IGF-1 receptor in radiation response. Transl Oncol. 2014;5(1):1–9.CrossRefGoogle Scholar
  236. Vara J, Casado E, de Castro J, Cejas P, Belda-Iniesta C, González-Barón M. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 2004;30(2):193–204.CrossRefGoogle Scholar
  237. Verbessem P, Lemiere J, Eijnde BO, Swinnen S, Vanhees L, Leemputte VM, Hespel P, Dom R. Creatine supplementation in Huntington’s disease: a placebo-controlled pilot trial. Neurology. 2003;61(7):925–30.PubMedCrossRefGoogle Scholar
  238. Vidal J-SS, Hanon O, Funalot B, Brunel N, Viollet C, Rigaud A-SS, Seux M-LL, le-Bouc Y, Epelbaum J and Duron E (2016). Low serum insulin-like growth factor-I predicts cognitive decline in Alzheimer’s disease. Journal of Alzheimer’s disease : JAD 52 (2): 641–649.Google Scholar
  239. Vives-Bauza C, Przedborski S. Mitophagy: the latest problem for Parkinson’s disease. Trends Mol Med. 2010;17(3):158–65.PubMedCrossRefGoogle Scholar
  240. Wang X, Fan H, Ying Z, Li B, Wang H, Wang G. Degradation of TDP-43 and its pathogenic form by autophagy and the ubiquitin-proteasome system. Neurosci Lett. 2010;469(1):112–6.PubMedCrossRefGoogle Scholar
  241. Warby SC, Doty CN, Graham RK, Shively J, Singaraja RR, Hayden MR. Phosphorylation of huntingtin reduces the accumulation of its nuclear fragments. Mol Cell Neurosci. 2009;40(2):121–7.PubMedCrossRefGoogle Scholar
  242. Wedler FC, Ley BW. Kinetic, ESR, and trapping evidence for in vivo binding of Mn(II) to glutamine synthetase in brain cells. Neurochem Res. 1994;19(2):139–44.PubMedCrossRefGoogle Scholar
  243. Weydert CJ, Waugh TA, Ritchie JM, Iyer KS, Smith JL, Li L, Spitz DR, Oberley LW. Overexpression of manganese or copper-zinc superoxide dismutase inhibits breast cancer growth. Free Radic Biol Med. 2006;41(2):226–37.PubMedCrossRefGoogle Scholar
  244. Weydt P, Pineda VV, Torrence AE, Libby RT, Satterfield TF, Lazarowski ER, Gilbert ML, Morton GJ, Bammler TK, Strand AD, Cui L, Beyer RP, Easley CN, Smith AC, Krainc D, Luquet S, Sweet IR, Schwartz MW, Spada AR. Thermoregulatory and metabolic defects in Huntington’s disease transgenic mice implicate PGC-1α in Huntington’s disease neurodegeneration. Cell Metab. 2006;4(5):349–62.PubMedCrossRefGoogle Scholar
  245. Williams A, Sarkar S, Cuddon P, Ttofi EK, Saiki S, Siddiqi FH, Jahreiss L, Fleming A, Pask D, Goldsmith P, O’Kane CJ, Floto R, Rubinsztein DC. Novel targets for Huntington’s disease in an mTOR-independent autophagy pathway. Nat Chem Biol. 2008;4(5):295–305.PubMedPubMedCentralCrossRefGoogle Scholar
  246. Williams BB, Kwakye GF, Wegrzynowicz M, Li D, Aschner M, Erikson KM, Bowman AB. Altered manganese homeostasis and manganese toxicity in a Huntington’s disease striatal cell model are not explained by defects in the iron transport system. Toxicol Sci. 2010a;117(1):169–79.PubMedPubMedCentralCrossRefGoogle Scholar
  247. Williams BB, Li D, Wegrzynowicz M, Vadodaria BK, Anderson JG, Kwakye GF, Aschner M, Erikson KM, Bowman AB. Disease-toxicant screen reveals a neuroprotective interaction between Huntington’s disease and manganese exposure. J Neurochem. 2010b;112(1):227–37.PubMedCrossRefGoogle Scholar
  248. Wolfe DM, Lee J, Kumar A, Lee S, Orenstein SJ, Nixon RA. Autophagy failure in Alzheimer’s disease and the role of defective lysosomal acidification. Eur J Neurosci. 2013;37(12):1949–61.PubMedPubMedCentralCrossRefGoogle Scholar
  249. Woźniak-Celmer E, Ołdziej S, Ciarkowski J. Theoretical models of catalytic domains of protein phosphatases 1 and 2A with Zn2+ and Mn2+ metal dications and putative bioligands in their catalytic centers. Acta Biochim Pol. 2001;48(1):35–52.PubMedGoogle Scholar
  250. Xiang Y, Ding N, Xing Z, Zhang W, Liu H, Li Z. Insulin-like growth factor-1 regulates neurite outgrowth and neuronal migration from Organotypic cultured dorsal root ganglion. Int J Neurosci. 2010;121(2):101–6.PubMedCrossRefGoogle Scholar
  251. Xing C, Yin Y, He X, Xie Z. Effects of insulin-like growth factor 1 on voltage-gated ion channels in cultured rat hippocampal neurons. Brain Res. 2006;1072(1):30–5.PubMedCrossRefGoogle Scholar
  252. Xing C, Yin Y, Chang R, Gong X, He X, Xie Z. Effects of insulin-like growth factor 1 on synaptic excitability in cultured rat hippocampal neurons. Exp Neurol. 2007;205(1):222–9.PubMedCrossRefGoogle Scholar
  253. Xiromerisiou G, Hadjigeorgiou GM, Papadimitriou A, Katsarogiannis E, Gourbali V, Singleton AB. Association between AKT1 gene and Parkinson’s disease: a protective haplotype. Neurosci Lett. 2008;436Google Scholar
  254. Xu B, Bird VG, Miller WT. Substrate specificities of the insulin and insulin-like growth factor 1 receptor tyrosine kinase catalytic domains. J Biol Chem. 1995;270(50):29825–30.PubMedCrossRefGoogle Scholar
  255. Xu Y, Liu C, Chen S, Ye Y, Guo M, Ren Q, Liu L, Zhang H, Xu C, Zhou Q. Activation of AMPK and inactivation of Akt result in suppression of mTOR-mediated S6K1 and 4E-BP1 pathways leading to neuronal cell death in in vitro models of Parkinson’s disease. Cell Signal. 2014;26Google Scholar
  256. Yamamoto A, Cremona ML, Rothman JE. Autophagy-mediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway. J Cell Biol. 2006;172(5):719–31.PubMedPubMedCentralCrossRefGoogle Scholar
  257. Yang D-S, Stavrides P, Mohan PS, Kaushik S, Kumar A, Ohno M, Schmidt SD, Wesson D, Bandyopadhyay U, Jiang Y, Pawlik M, Peterhoff CM, Yang AJ, Wilson DA, George-Hyslop P, Westaway D, Mathews PM, Levy E, Cuervo AM, Nixon RA. Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer’s disease ameliorates amyloid pathologies and memory deficits. Brain J Neurol. 2011;134(Pt 1):258–77.CrossRefGoogle Scholar
  258. Yu HW, Cuervo A, Kumar A, Peterhoff CM, Schmidt SD, Lee J-H, Mohan PS, Mercken M, Farmery MR, Tjernberg LO. Macroautophagy—a novel β-amyloid peptide-generating pathway activated in Alzheimer’s disease. J Cell Biol. 2005;171Google Scholar
  259. Zala D, Colin E, Rangone H, Liot G, Humbert S, Saudou F. Phosphorylation of mutant huntingtin at S421 restores anterograde and retrograde transport in neurons. Hum Mol Genet. 2008;17(24):3837–46.PubMedCrossRefGoogle Scholar
  260. Zhang D, Kanthasamy A, Anantharam V, Kanthasamy A. Effects of manganese on tyrosine hydroxylase (TH) activity and TH-phosphorylation in a dopaminergic neural cell line. Toxicol Appl Pharmacol. 2011;254(2):65–71.PubMedPubMedCentralCrossRefGoogle Scholar
  261. Zhang J, Cao R, Cai T, Aschner M, Zhao F, Yao T, Chen Y, Cao Z, Luo W, Chen J. The role of autophagy dysregulation in manganese-induced dopaminergic neurodegeneration. Neurotox Res. 2013;24(4):478–90.PubMedPubMedCentralCrossRefGoogle Scholar
  262. Zhang Z, Miah M, Culbreth M, Aschner M. Autophagy in neurodegenerative diseases and metal neurotoxicity. Neurochem Res. 2016;41(1–2):409–22.PubMedCrossRefGoogle Scholar
  263. Zhao W, Chen H, Xu H, Moore E, Meiri N, Quon MJ, Alkon DL. Brain insulin receptors and spatial memory. Correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats. J Biol Chem. 1999;274(49):34893–902.PubMedCrossRefGoogle Scholar
  264. Zhou T, Chou J, Zhou Y, Simpson DA, Cao F, Bushel PR, Paules RS, Kaufmann WK. Ataxia telangiectasia-mutated dependent DNA damage checkpoint functions regulate gene expression in human fibroblasts. Mol Cancer Res MCR. 2007;5(8):813–22.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of NeurologyVanderbilt University Medical CenterNashvilleUSA
  2. 2.Vanderbilt Brain InstituteVanderbilt University Medical CenterNashvilleUSA
  3. 3.Department of PediatricsVanderbilt University Medical CenterNashvilleUSA
  4. 4.Vanderbilt Center in Molecular ToxicologyVanderbilt University Medical CenterNashvilleUSA

Personalised recommendations