A novel manganese-dependent ATM-p53 signaling pathway is selectively impaired in patient-based neuroprogenitor and murine striatal models of Huntington's disease

Human Molecular Genetics

Volumn 24, Issue 7, 2014, Pages 1929-1944

  Tidball, Andrew M ^a,b   Bryan, Miles R ^a,b   Uhouse, Michael A ^a   Kumar, Kevin K ^a,b   Aboud, Asad A ^a,b   Feist, Jack E ^a   Ess, Kevin C ^a,b   Diana Neely, M ^a,b   Aschner, Michael ^c   Bowman, Aaron B ^a,b  

^a VANDERBILT UNIVERSITY MEDICAL CENTER   (United States)

^b VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c ALBERT EINSTEIN COLLEGE OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ATM PROTEIN; CHECKPOINT KINASE 2; HISTONE H2AX; MANGANESE; PROTEIN P53; SERINE;

ANIMAL CELL; ARTICLE; AUTOPHOSPHORYLATION; BASAL GANGLION; BIOACCUMULATION; CONTROLLED STUDY; CORPUS STRIATUM; DNA DAMAGE; HUMAN; HUMAN CELL; HUNTINGTON CHOREA; MOUSE; NEURAL STEM CELL; NONHUMAN; OXIDATIVE STRESS; PHENOTYPE; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; SIGNAL TRANSDUCTION; ANIMAL; CELL LINE; CHEMISTRY; DISEASE MODEL; ENZYMOLOGY; FEMALE; GENETICS; MALE; METABOLISM; PHOSPHORYLATION; PROTEIN MOTIF;

MURINAE;

AMINO ACID MOTIFS; ANIMALS; ATAXIA TELANGIECTASIA MUTATED PROTEINS; CELL LINE; CORPUS STRIATUM; DISEASE MODELS, ANIMAL; DNA DAMAGE; FEMALE; HUMANS; HUNTINGTON DISEASE; MALE; MANGANESE; MICE; NEURAL STEM CELLS; PHOSPHORYLATION; SIGNAL TRANSDUCTION; TUMOR SUPPRESSOR PROTEIN P53;

EID: 84926435051     PISSN: 09646906     EISSN: 14602083     Source Type: Journal    
DOI: 10.1093/hmg/ddu609     Document Type: Article

References (81)

1. Zuccato, C., Valenza, M. and Cattaneo, E. (2010) Molecular mechanisms and potential therapeutical targets in Huntington's disease. Physiol. Rev., 90, 905-981.
2. Wexler, N.S. (2004) Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset. Proc. Natl. Acad. Sci. U. S. A., 101, 3498-3503.
3. Gusella, J.F. and MacDonald, M.E. (2009) Huntington's disease:the case for genetic modifiers. Genome Med., 1, 80.
4. Georgiou, N., Bradshaw, J.L., Chiu, E., Tudor, A., O'Gorman, L. and Phillips, J.G. (1999) Differential clinical and motor control function in a pair of monozygotic twins with Huntington's disease. Mov. Disord., 14, 320-325.
5. Anca, M., Gazit, E., Loewenthal, R., Ostrovsky, O., Frydman, M. and Giladi, N. (2004) Different phenotypic expression in monozygotic twins with Huntington disease. Am. J. Med. Genet. A, 124, 89-91.
6. Friedman, J.H., Trieschmann, M.E., Myers, R.H. and Fernandez, H.H. (2005) Monozygotic twins discordant for Huntington disease after 7 years. Arch. Neurol., 62, 995-997.
7. Glass, M., Van Dellen, A., Blakemore, C., Hannan, A. and Faull, R. (2004) Delayed onset of huntington's disease in mice in an enriched environment correlates with delayed loss of cannabinoid CB1 receptors. Neuroscience, 123, 207-212.
8. Fox, J.H., Kama, J.A., Lieberman, G., Chopra, R., Dorsey, K., Chopra, V., Volitakis, I., Cherny, R.A., Bush, A.I. and Hersch, S. (2007) Mechanisms of copper ion mediated Huntington's disease progression. PLoS One, 2, e334.
9. Xiao, G., Fan, Q.,Wang, X. and Zhou, B. (2013) Huntington disease arises from a combinatory toxicity of polyglutamine and copper binding. Proc. Natl. Acad. Sci. USA, 110, 14995-15000.
10. Wild, E.J. and Tabrizi, S.J. (2007) Huntington's disease phenocopy syndromes. Curr. Opin. Neurol., 20, 681-687.
11. Williams, B.B., Li, D.,Wegrzynowicz, M., Vadodaria, B.K., Anderson, J.G., Kwakye, G.F., Aschner, M., Erikson, K.M. and Bowman, A.B. (2010) Disease-toxicant screen reveals a neuroprotective interaction between Huntington's disease and manganese exposure. J. Neurochem., 112, 227-237.
12. Trettel, F., Rigamonti, D., Hilditch-Maguire, P., Wheeler, V.C., Sharp, A.H., Persichetti, F., Cattaneo, E. and MacDonald, M.E. (2000) Dominant phenotypes produced by the HD mutation in STHdhQ111 striatal cells. Hum. Mol. Genet., 9, 2799-2809.
13. Aschner, J.L. and Aschner, M. (2005) Nutritional aspects of manganese homeostasis. Mol. Aspects Med., 26, 353-362.
14. Bowman, A.B., Kwakye, G.F., Herrero Hernández, E. and Aschner, M. (2011) Role of manganese in neurodegenerative diseases. J. Trace Elem. Med. Biol., 25, 191-203.
15. Zhang, S., Fu, J. and Zhou, Z. (2004) In vitro effect of manganese chloride exposure on reactive oxygen species generation and respiratory chain complexes activities of mitochondria isolated from rat brain. Toxicol. In Vitro, 18, 71-77.
16. Santamaria, A. (2008) Manganese exposure, essentiality & toxicity. Indian J. Med. Res., 128, 484.
17. Larsen, N.A., Pakkenberg, H., Damsgaard, E. and Heydorn, K. (1979) Topographical distribution of arsenic, manganese, and selenium in the normal human brain. J. Neurol. Sci., 42, 407-416.
18. Prohaska, J.R. (1987) Functions of trace elements in brain metabolism. Physiol. Rev., 67, 858-901.
19. Madison, J.L., Wegrzynowicz, M., Aschner, M. and Bowman, A.B. (2012) Disease-toxicant interactions in manganese exposed Huntington disease mice: early changes in striatal neuron morphology and dopamine metabolism. PLoS One, 7, e31024.
20. Rosas, H.D., Chen, Y.I., Doros, G., Salat, D.H., Chen, N.-K., Kwong, K.K., Bush, A., Fox, J. and Hersch, S.M. (2012) Alterations in brain transition metals in Huntington disease: an evolving and intricate story. Arch. Neurol., 69, 887-893.
21. Okita, K., Matsumura, Y., Sato, Y., Okada, A., Morizane, A., Okamoto, S., Hong, H., Nakagawa, M., Tanabe, K. and Tezuka, K.-I. (2011) A more efficient method to generate integrationfree human iPS cells. Nat. Methods, 8, 409-412.
22. Chambers, S.M., Fasano, C.A., Papapetrou, E.P., Tomishima, M., Sadelain, M. and Studer, L. (2009) Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat. Biotechnol., 27, 275-280.
23. Ma, L., Hu, B., Liu, Y., Vermilyea, S.C., Liu, H., Gao, L., Sun, Y., Zhang, X. and Zhang, S.-C. (2012) Human embryonic stem cell-derived GABA neurons correct locomotion deficits in quinolinic acid-lesioned mice. Cell Stem Cell, 10, 455-464.
24. Carri, A.D., Onorati, M., Lelos, M.J., Castiglioni, V., Faedo, A., Menon, R., Camnasio, S., Vuono, R., Spaiardi, P. and Talpo, F. (2013) Developmentally coordinated extrinsic signals drive human pluripotent stem cell differentiation toward authentic DARPP-32+ medium-sized spiny neurons. Development, 140, 301-312.
25. Guo, X., Disatnik, M.-H., Monbureau, M., Shamloo, M., Mochly-Rosen, D. and Qi, X. (2013) Inhibition of mitochondrial fragmentation diminishes Huntington's disease-associated neurodegeneration. J. Clin. Invest., 123, 5371-5388.
26. Zhang, N., An, M.C., Montoro, D. and Ellerby, L.M. (2010) Characterization of human Huntington's disease cell model from induced pluripotent stem cells. PLoS Curr., 2.
27. Camnasio, S., Carri, A.D., Lombardo, A., Grad, I., Mariotti, C., Castucci, A., Rozell, B., Riso, P.L., Castiglioni, V. and Zuccato, C. (2012) The first reported generation of several induced pluripotent stem cell lines from homozygous and heterozygous Huntington's disease patients demonstrates mutation related enhanced lysosomal activity. Neurobiol. Dis., 46, 41-51.
28. Consortium, H.I. (2012) Induced pluripotent stem cells from patients with Huntington's disease show CAG-repeatexpansion- associated phenotypes. Cell Stem Cell, 11, 264-278.
29. Juopperi, T.A., Kim,W.R., Chiang, C.-H., Yu, H., Margolis, R.L., Ross, C.A., Ming, G. and Song, H. (2012) Astrocytes generated from patient induced pluripotent stem cells recapitulate features of Huntington's disease patient cells. Mol. Brain, 5, 17.
30. Castiglioni, V., Onorati, M., Rochon, C. and Cattaneo, E. (2012) Induced pluripotent stem cell lines from Huntington's disease mice undergo neuronal differentiation while showing alterations in the lysosomal pathway. Neurobiol. Dis., 46, 30-40.
31. Gines, S., Seong, I.S., Fossale, E., Ivanova, E., Trettel, F., Gusella, J.F., Wheeler, V.C., Persichetti, F. and MacDonald, M.E. (2003) Specific progressive cAMP reduction implicates energy deficit in presymptomatic Huntington's disease knock-in mice. Hum. Mol. Genet., 12, 497-508.
32. Weydt, P., Pineda, V.V., Torrence, A.E., Libby, R.T., Satterfield, T.F., Lazarowski, E.R., Gilbert, M.L., Morton, G.J., Bammler, T.K. and Strand, A.D. (2006) Thermoregulatory and metabolic defects in Huntington's disease transgenic mice implicate PGC-1α in Huntington's disease neurodegeneration. Cell Metab., 4, 349-362.
33. Mochel, F., Durant, B., Meng, X., O'Callaghan, J., Yu, H., Brouillet, E., Wheeler, V.C., Humbert, S., Schiffmann, R. and Durr, A. (2012) Early alterations of brain cellular energy homeostasis in Huntington disease models. J. Biol. Chem., 287, 1361-1370.
34. Seong, I.S., Ivanova, E., Lee, J.-M., Choo, Y.S., Fossale, E., Anderson, M., Gusella, J.F., Laramie, J.M., Myers, R.H. and Lesort, M. (2005) HD CAG repeat implicates a dominant property of huntingtin in mitochondrial energy metabolism. Hum. Mol. Genet., 14, 2871-2880.
35. Nagata, E., Sawa, A., Ross, C.A. and Snyder, S.H. (2004) Autophagosome- like vacuole formation in Huntington's disease lymphoblasts. Neuroreport., 15, 1325-1328.
36. Martinez-Vicente, M., Talloczy, Z., Wong, E., Tang, G., Koga, H., Kaushik, S., de Vries, R., Arias, E., Harris, S. and Sulzer, D. (2010) Cargo recognition failure is responsible for inefficient autophagy in Huntington's disease. Nat. Neurosci., 13, 567-576.
37. Cordova, F.M., Aguiar, A.S. Jr, Peres, T.V., Lopes, M.W., Gonçalves, F.M., Remor, A.P., Lopes, S.C., Pilati, C., Latini, A.S. and Prediger, R.D. (2012) In vivo manganese exposure modulates Erk, Akt and Darpp-32 in the striatum of developing rats, and impairs their motor function. PLoS One, 7, e33057.
38. Bae, J.-H., Jang, B.-C., Suh, S.-I., Ha, E., Baik, H.H., Kim, S.-S., Lee, M.-Y. and Shin, D.-H. (2006) Manganese induces inducible nitric oxide synthase (iNOS) expression via activation of both MAP kinase and PI3 K/Akt pathways in BV2 microglial cells. Neurosci. Lett., 398, 151-154.
39. Guilarte, T.R., Burton, N.C., Verina, T., Prabhu, V.V., Becker, K. G., Syversen, T. and Schneider, J.S. (2008) Increased APLP1 expression and neurodegeneration in the frontal cortex of manganese- exposed non-human primates. J. Neurochem., 105, 1948-1959.
40. Zhao, F., Zhang, J.-B., Cai, T.-J., Liu, X.-Q., Liu, M.-C., Ke, T., Chen, J.-Y. and Luo, W.-J. (2012) Manganese induces p21 expression in PC12 cells at the transcriptional level. Neuroscience, 215, 184-195.
41. Colin, E., Régulier, E., Perrin, V., Dürr, A., Brice, A., Aebischer, P., Déglon, N., Humbert, S. and Saudou, F. (2005) Akt is altered in an animal model of Huntington's disease and in patients. Eur. J. Neurosci., 21, 1478-1488.
42. Humbert, S., Bryson, E.A., Cordelières, F.P., Connors, N.C., Datta, S.R., Finkbeiner, S., Greenberg, M.E. and Saudou, F. (2002) The IGF-1/Akt pathway is neuroprotective in Huntington's disease and involves Huntingtin phosphorylation by Akt. Dev. Cell, 2, 831-837.
43. Bae, B.-I., Xu, H., Igarashi, S., Fujimuro, M., Agrawal, N., Taya, Y., Hayward, S.D., Moran, T.H., Montell, C. and Ross, C.A. (2005) p53 mediates cellular dysfunction and behavioral abnormalities in Huntington's disease. Neuron, 47, 29-41.
44. Steffan, J.S., Kazantsev, A., Spasic-Boskovic, O., Greenwald, M., Zhu, Y.-Z., Gohler, H.,Wanker, E.E., Bates, G.P., Housman, D.E. and Thompson, L.M. (2000) The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription. Proc. Natl. Acad. Sci. USA, 97, 6763-6768.
45. Apostol, B.L., Illes, K., Pallos, J., Bodai, L.,Wu, J., Strand, A., Schweitzer, E.S., Olson, J.M., Kazantsev, A. and Marsh, J.L. (2006) Mutant huntingtin alters MAPK signaling pathways in PC12 and striatal cells: ERK1/2 protects against mutant huntingtin-associated toxicity. Hum. Mol. Genet., 15, 273-285.
46. Fan, J., Gladding, C.M., Wang, L., Zhang, L.Y., Kaufman, A.M., Milnerwood, A.J. and Raymond, L.A. (2012) P38 MAPK is involved in enhanced NMDA receptor-dependent excitotoxicity in YAC transgenic mouse model of Huntington disease. Neurobiol. Dis., 45, 999-1009.
47. Ravikumar, B., Vacher, C., Berger, Z., Davies, J.E., Luo, S., Oroz, L.G., Scaravilli, F., Easton, D.F., Duden, R. and O'Kane, C.J. (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet., 36, 585-595.
48. Ju, T.-C., Chen, H.-M., Lin, J.-T., Chang, C.-P., Chang,W.-C., Kang, J.-J., Sun, C.-P., Tao, M.-H., Tu, P.-H. and Chang, C. (2011) Nuclear translocation of AMPK-α1 potentiates striatal neurodegeneration in Huntington's disease. J. Cell Biol., 194, 209-227.
49. Carmichael, J., Sugars, K.L., Bao, Y.P. and Rubinsztein, D.C. (2002) Glycogen synthase kinase-3β inhibitors prevent cellular polyglutamine toxicity caused by the Huntington,s disease mutation. J. Biol. Chem., 277, 33791-33798.
50. Ku, S., Soragni, E., Campau, E., Thomas, E.A., Altun, G., Laurent, L.C., Loring, J.F., Napierala, M. and Gottesfeld, J.M. (2010) Friedreich's ataxia induced pluripotent stem cells model intergenerational GAA· TTC triplet repeat instability. Cell Stem Cell, 7, 631-637.
51. Manley, K., Shirley, T.L., Flaherty, L. and Messer, A. (1999) Msh2 deficiency prevents in vivo somatic instability of the CAG repeat in Huntington disease transgenic mice. Nat. Genet., 23, 471-473.
52. Neely, M.D., Litt, M.J., Tidball, A.M., Li, G.G., Aboud, A.A., Hopkins, C.R., Chamberlin, R., Hong, C.C., Ess, K.C. and Bowman, A.B. (2012) DMH1, a highly selective small molecule BMP inhibitor promotes neurogenesis of hiPSCs: comparison of PAX6 and Sox1 expression during neural induction. ACS Chem. Neurosci., 3, 482-491.
53. Zhang, X., Huang, C.T., Chen, J., Pankratz, M.T., Xi, J., Li, J., Yang, Y., LaVaute, T.M., Li, X.-J. and Ayala, M. (2010) Pax6 is a human neuroectoderm cell fate determinant. Cell Stem Cell, 7, 90-100.
54. Wang, H.-F. and Liu, F.-C. (2001) Developmental restriction of the LIM homeodomain transcription factor Islet-1 expression to cholinergic neurons in the rat striatum. Neuroscience, 103, 999-1016.
55. López-Bendito, G., Cautinat, A., Sánchez, J.A., Bielle, F., Flames, N., Garratt, A.N., Talmage, D.A., Role, L.W., Charnay, P. and Marín, O. (2006) Tangential neuronal migration controls axon guidance: a role for neuregulin-1 in thalamocortical axon navigation. Cell, 125, 127-142.
56. Bowman, A.B. and Aschner, M. (2014) Considerations on manganese (Mn) treatments for in vitro studies. Neurotoxicology, 41, 141-142.
57. Williams, B.B.,Kwakye, G.F.,Wegrzynowicz,M., Li,D., Aschner, M., Erikson, K.M. and Bowman, A.B. (2010) Alteredmanganese homeostasis and manganese toxicity in a Huntington's disease striatal cell model are not explained by defects in the iron transport system. Toxicol. Sci., 117, 169-179.
58. Banin, S., Moyal, L., Shieh, S.-Y., Taya, Y., Anderson, C., Chessa, L., Smorodinsky, N., Prives, C., Reiss, Y. and Shiloh, Y. (1998) Enhanced phosphorylation of p53 by ATM in response to DNA damage. Science, 281, 1674-1677.
59. Canman, C.E., Lim, D.-S., Cimprich, K.A., Taya, Y., Tamai, K., Sakaguchi, K., Appella, E., Kastan, M.B. and Siliciano, J.D. (1998) Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science, 281, 1677-1679.
60. Jones, R.G., Plas, D.R., Kubek, S., Buzzai, M., Mu, J., Xu, Y., Birnbaum, M.J. and Thompson, C.B. (2005) AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol. Cell, 18, 283-293.
61. She, Q.-B., Chen, N. and Dong, Z. (2000) ERKs and p38 kinase phosphorylate p53 protein at serine 15 in response to UV radiation. J. Biol. Chem., 275, 20444-20449.
62. Chan, D.W., Son, S.-C., Block, W., Ye, R., Khanna, K.K., Wold, M.S., Douglas, P., Goodarzi, A.A., Pelley, J. and Taya, Y. (2000) Purification and Characterization of ATM from Human Placenta a Manganese-Dependent, Wortmannin-Sensitive Serine/ Threonine Protein Kinase. J. Biol. Chem., 275, 7803-7810.
63. Guo, Z., Kozlov, S., Lavin, M.F., Person, M.D. and Paull, T.T. (2010) ATM activation by oxidative stress. Science, 330, 517-521.
64. Bakkenist, C.J. and Kastan, M.B. (2003) DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature, 421, 499-506.
65. Hickson, I., Zhao, Y., Richardson, C.J., Green, S.J., Martin, N.M., Orr, A.I., Reaper, P.M., Jackson, S.P., Curtin, N.J. and Smith, G. C. (2004) Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Res., 64, 9152-9159.
66. Kwakye, G.F., Li, D. and Bowman, A.B. (2011) Novel highthroughput assay to assess cellular manganese levels in a striatal cell line model of Huntington's disease confirms a deficit in manganese accumulation. Neurotoxicology, 32, 630-639.
67. Kumar, K.K., Aboud, A.A., Patel, D.K., Aschner, M. and Bowman, A.B. (2013) Optimization of Fluorescence Assay of cellular manganese status for high throughput screening. J. Biochem. Mol. Toxicol., 27, 42-49.
68. Waghorn, B., Yang, Y., Baba, A., Matsuda, T., Schumacher, A., Yanasak, N. and Hu, T.C.C. (2009) Assessing manganese efflux using SEA0400 and cardiac T1-mapping manganeseenhanced MRI in a murine model. NMR Biomed., 22, 874-881.
69. Dally, H. and Hartwig, A. (1997) Induction and repair inhibition of oxidative DNA damage by nickel (II) and cadmium (II) in mammalian cells. Carcinogenesis, 18, 1021-1026.
70. Kumar, K.K., Lowe, J.E.W., Aboud, A.A., Neely, M.D., Redha, R., Bauer, J.A., Odak, M.,Weaver, C.D., Meiler, J., Aschner, M. et al. (2014) Cellular manganese content is developmentally regulated in human dopaminergic neurons. Sci. Rep., 4, 1-8.
71. Ferlazzo, M.L., Sonzogni, L., Granzotto, A., Bodgi, L., Lartin, O., Devic, C., Vogin, G., Pereira, S. and Foray, N. (2013) Mutations of the Huntington's Disease Protein Impact on the ATM-Dependent Signaling and Repair Pathways of the Radiation-Induced DNA Double-Strand Breaks: Corrective Effect of Statins and Bisphosphonates. Mol. Neurobiol., 49, 1-12.
72. Jung-Il, C., Dong-Wook, K., Nayeon, L., Young-Joo, J., Iksoo, J., Jihye, K., Jumi, K., Yunjo, S., Dong-Seok, L. and Kang, S.S. (2012) Quantitative proteomic analysis of induced pluripotent stem cells derived from a human Huntington's disease patient. Biochem. J., 446, 359-371.
73. Ehrnhoefer, D.E., Skotte, N.H., Ladha, S., Nguyen, Y.T., Qiu, X., Deng, Y., Huynh, K.T., Engemann, S., Nielsen, S.M. and Becanovic, K. (2014) p53 increases caspase-6 expression and activation in muscle tissue expressing mutant huntingtin. Hum. Mol. Genet., 23, 717-729.
74. Chattopadhyay, B., Baksi, K., Mukhopadhyay, S. and Bhattacharyya, N.P. (2005) Modulation of age at onset of Huntington disease patients by variations in TP53 and human caspase activated DNase (hCAD) genes. Neurosci. Lett., 374, 81-86.
75. Helton, E.S. and Chen, X. (2007) p53 modulation of the DNA damage response. J. Cell. Biochem., 100, 883-896.
76. Kalia, K., Jiang,W. and Zheng,W. (2008) Manganese accumulates primarily in nuclei of cultured brain cells. Neurotoxicology, 29, 466-470.
77. Morello, M., Canini, A., Mattioli, P., Sorge, R., Alimonti, A., Bocca, B., Forte, G., Martorana, A., Bernardi, G. and Sancesario, G. (2008) 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, 29, 60-72.
78. Chiang, M.-C., Chen, H.-M., Lee, Y.-H., Chang, H.-H., Wu, Y.-C., Soong, B.-W., Chen, C.-M., Wu, Y.-R., Liu, C.-S. and Niu, D.-M. (2007) Dysregulation of C/EBPOE± by mutant Huntingtin causes the urea cycle deficiency in Huntington's disease. Hum. Mol. Genet., 16, 483-498.
79. Lievens, J.-C., Woodman, B., Mahal, A., Spasic-Boscovic, O., Samuel, D., Kerkerian-Le Goff, L. and Bates, G. (2001) Impaired glutamate uptake in the R6 Huntington's disease transgenic mice. Neurobiol. Dis., 8, 807-821.
80. Podolsky, S., Leopold, N. and Sax, D. (1972) Increased frequency of diabetes mellitus in patients with Huntington's chorea. Lancet, 299, 1356-1359.
81. Müller, F.-J., Schuldt, B.M., Williams, R., Mason, D., Altun, G., Papapetrou, E.P., Danner, S., Goldmann, J.E., Herbst, A. and Schmidt, N.O. (2011) A bioinformatic assay for pluripotency in human cells. Nat. Methods, 8, 315-317.