Molecular Neurobiology

, Volume 47, Issue 3, pp 1093–1102 | Cite as

DNA Repair Mechanisms in Huntington’s Disease

Article

Abstract

The human genome is under continuous attack by a plethora of harmful agents. Without the development of several dedicated DNA repair pathways, the genome would have been destroyed and cell death, inevitable. However, while DNA repair enzymes generally maintain the integrity of the whole genome by properly repairing mutagenic and cytotoxic intermediates, there are cases in which the DNA repair machinery is implicated in causing disease rather than protecting against it. One case is the instability of gene-specific trinucleotides, the causative mutations of numerous disorders including Huntington’s disease. The DNA repair proteins induce mutations that are different from the genome-wide mutations that arise in the absence of repair enzymes; they occur at definite loci, they occur in specific tissues during development, and they are age-dependent. These latter characteristics make pluripotent stem cells a suitable model system for triplet repeat expansion disorders. Pluripotent stem cells can be kept in culture for a prolonged period of time and can easily be differentiated into any tissue, e.g., cells along the neural lineage. Here, we review the role of DNA repair proteins in the process of triplet repeat instability in Huntington’s disease and also the potential use of pluripotent stem cells to investigate neurodegenerative disorders.

Keywords

Huntington’s disease Dementia DNA repair Induced pluripotent stem cells 

References

  1. 1.
    Vonsattel JP, DiFiglia M (1998) Huntington disease. J Neuropathol Exp Neurol 57(5):369–384PubMedCrossRefGoogle Scholar
  2. 2.
    Imarisio S, Carmichael J, Korolchuk V, Chen CW, Saiki S, Rose C et al (2008) Huntington's disease: from pathology and genetics to potential therapies. Biochem J 412(2):191–209PubMedCrossRefGoogle Scholar
  3. 3.
    Anonymous 1993 A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group. Cell 72(6):971–83Google Scholar
  4. 4.
    Walker FO (2007) Huntington's disease. Semin Neurol 27(2):143–150PubMedCrossRefGoogle Scholar
  5. 5.
    Walker FO (2007) Huntington's disease. Lancet 369(9557):218–228PubMedCrossRefGoogle Scholar
  6. 6.
    Rubinsztein DC, Leggo J, Coles R, Almqvist E, Biancalana V, Cassiman JJ et al (1996) Phenotypic characterization of individuals with 30–40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36–39 repeats. Am J Hum Genet 59(1):16–22PubMedGoogle Scholar
  7. 7.
    Gil JM, Rego AC (2008) Mechanisms of neurodegeneration in Huntington's disease. Eur J Neurosci 27(11):2803–2820PubMedCrossRefGoogle Scholar
  8. 8.
    Martin JB (1999) Molecular basis of the neurodegenerative disorders. N Engl J Med 340(25):1970–1980PubMedCrossRefGoogle Scholar
  9. 9.
    Sieradzan KA, Mann DM (2001) The selective vulnerability of nerve cells in Huntington's disease. Neuropathol Appl Neurobiol 27(1):1–21PubMedCrossRefGoogle Scholar
  10. 10.
    Ridley RM, Frith CD, Crow TJ, Conneally PM (1988) Anticipation in Huntington's disease is inherited through the male line but may originate in the female. J Med Genet 25(9):589–595PubMedCrossRefGoogle Scholar
  11. 11.
    Wheeler VC, Lebel LA, Vrbanac V, Teed A (2003) te RH, MacDonald ME. Mismatch repair gene Msh2 modifies the timing of early disease in Hdh(Q111) striatum. Hum Mol Genet 12(3):273–281PubMedCrossRefGoogle Scholar
  12. 12.
    Dragileva E, Hendricks A, Teed A, Gillis T, Lopez ET, Friedberg EC et al (2009) Intergenerational and striatal CAG repeat instability in Huntington's disease knock-in mice involve different DNA repair genes. Neurobiol Dis 33(1):37–47PubMedCrossRefGoogle Scholar
  13. 13.
    Kovtun IV, Liu Y, Bjoras M, Klungland A, Wilson SH, McMurray CT (2007) OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells. Nature 447(7143):447–452PubMedCrossRefGoogle Scholar
  14. 14.
    Wang X, Michaelis EK (2010) Selective neuronal vulnerability to oxidative stress in the brain. Front Aging Neurosci 2:12PubMedGoogle Scholar
  15. 15.
    Hochedlinger K, Plath K (2009) Epigenetic reprogramming and induced pluripotency. Development 136(4):509–523PubMedCrossRefGoogle Scholar
  16. 16.
    Yu J, Vodyanik MA, Smuga-Otto K, Ntosiewicz-Bourget J, Frane JL, Tian S et al (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318(5858):1917–1920PubMedCrossRefGoogle Scholar
  17. 17.
    Wernig M, Meissner A, Foreman R, Brambrink T, Ku M, Hochedlinger K et al (2007) In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448(7151):318–324PubMedCrossRefGoogle Scholar
  18. 18.
    Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4):663–676PubMedCrossRefGoogle Scholar
  19. 19.
    Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5):861–872PubMedCrossRefGoogle Scholar
  20. 20.
    Jung CB, Moretti A, Schnitzler M, Iop L, Storch U, Bellin M et al (2012) Dantrolene rescues arrhythmogenic RYR2 defect in a patient-specific stem cell model of catecholaminergic polymorphic ventricular tachycardia. EMBO Mol Med 4(3):180–191PubMedCrossRefGoogle Scholar
  21. 21.
    Koch P, Breuer P, Peitz M, Jungverdorben J, Kesavan J, Poppe D et al (2011) Excitation-induced ataxin-3 aggregation in neurons from patients with Machado–Joseph disease. Nature 480(7378):543–546PubMedGoogle Scholar
  22. 22.
    Moretti A, Bellin M, Welling A, Jung CB, Lam JT, Bott-Flugel L et al (2010) Patient-specific induced pluripotent stem-cell models for long-QT syndrome. N Engl J Med 363(15):1397–1409PubMedCrossRefGoogle Scholar
  23. 23.
    Israel MA, Yuan SH, Bardy C, Reyna SM, Mu Y, Herrera C et al (2012) Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells. Nature 482(7384):216–220PubMedGoogle Scholar
  24. 24.
    An MC, Zhang N, Scott G, Montoro D, Wittkop T, Mooney S et al (2012) Genetic correction of Huntington's disease Phenotypes in induced pluripotent stem cells. Cell Stem Cell 11(2):253–263PubMedCrossRefGoogle Scholar
  25. 25.
    Zhang N, An MC, Montoro D, Ellerby LM (2010) Characterization of human Huntington's Disease cell model from induced pluripotent stem cells. PLoS Curr ;2:RRN1193Google Scholar
  26. 26.
    Friedberg EC (2006) DNA Repair and mutagenesis, 2nd edn. Washington, ASMGoogle Scholar
  27. 27.
    Lindahl T (1993) Instability and decay of the primary structure of DNA. Nature 362(6422):709–715PubMedCrossRefGoogle Scholar
  28. 28.
    Rouse J, Jackson SP (2002) Interfaces between the detection, signaling, and repair of DNA damage. Science 297(5581):547–551PubMedCrossRefGoogle Scholar
  29. 29.
    Zhou BB, Elledge SJ (2000) The DNA damage response: putting checkpoints in perspective. Nature 408(6811):433–439PubMedCrossRefGoogle Scholar
  30. 30.
    Rich T, Allen RL, Wyllie AH (2000) Defying death after DNA damage. Nature 407(6805):777–783PubMedCrossRefGoogle Scholar
  31. 31.
    Falnes PO, Rognes T (2003) DNA repair by bacterial AlkB proteins. Res Microbiol 154(8):531–538PubMedCrossRefGoogle Scholar
  32. 32.
    Fu D, Calvo JA, Samson LD (2012) Balancing repair and tolerance of DNA damage caused by alkylating agents. Nat Rev Cancer 12(2):104–120PubMedGoogle Scholar
  33. 33.
    Goula AV, Berquist BR, Wilson DM III, Wheeler VC, Trottier Y, Merienne K (2009) Stoichiometry of base excision repair proteins correlates with increased somatic CAG instability in striatum over cerebellum in Huntington's disease transgenic mice. PLoS Genet 5(12):e1000749PubMedCrossRefGoogle Scholar
  34. 34.
    De LG, Russo MT, Degan P, Tiveron C, Zijno A, Meccia E et al (2008) A role for oxidized DNA precursors in Huntington's disease-like striatal neurodegeneration. PLoS Genet 4(11):e1000266CrossRefGoogle Scholar
  35. 35.
    Shirendeb U, Reddy AP, Manczak M, Calkins MJ, Mao P, Tagle DA et al (2011) Abnormal mitochondrial dynamics, mitochondrial loss and mutant Huntingtin oligomers in Huntington's disease: implications for selective neuronal damage. Hum Mol Genet 20(7):1438–1455PubMedCrossRefGoogle Scholar
  36. 36.
    Butterworth NJ, Williams L, Bullock JY, Love DR, Faull RL, Dragunow M (1998) Trinucleotide (CAG) repeat length is positively correlated with the degree of DNA fragmentation in Huntington's disease striatum. Neuroscience 87(1):49–53PubMedCrossRefGoogle Scholar
  37. 37.
    Crick F (1974) The double helix: a personal view. Nature 248(5451):766–769PubMedCrossRefGoogle Scholar
  38. 38.
    Wood RD, Mitchell M, Lindahl T (2005) Human DNA repair genes, 2005. Mutat Res 577(1–2):275–283PubMedGoogle Scholar
  39. 39.
    Eisen JA, Hanawalt PC (1999) A phylogenomic study of DNA repair genes, proteins, and processes. Mutat Res 435(3):171–213PubMedCrossRefGoogle Scholar
  40. 40.
    Robertson AB, Klungland A, Rognes T, Leiros I (2009) DNA repair in mammalian cells: base excision repair: the long and short of it. Cell Mol Life Sci 66(6):981–993PubMedCrossRefGoogle Scholar
  41. 41.
    Larsen E, Meza TJ, Kleppa L, Klungland A (2007) Organ and cell specificity of base excision repair mutants in mice. Mutat Res 614(1–2):56–68PubMedGoogle Scholar
  42. 42.
    Lindahl T, Wood RD (1999) Quality control by DNA repair. Science 286(5446):1897–1905PubMedCrossRefGoogle Scholar
  43. 43.
    Krokan HE, Standal R, Slupphaug G (1997) DNA glycosylases in the base excision repair of DNA. Biochem J 325(Pt 1):1–16PubMedGoogle Scholar
  44. 44.
    Matsumoto Y, Kim K (1995) Excision of deoxyribose phosphate residues by DNA polymerase beta during DNA repair. Science 269(5224):699–702PubMedCrossRefGoogle Scholar
  45. 45.
    Kubota Y, Nash RA, Klungland A, Schar P, Barnes DE, Lindahl T (1996) Reconstitution of DNA base excision-repair with purified human proteins: interaction between DNA polymerase beta and the XRCC1 protein. EMBO J 15(23):6662–6670PubMedGoogle Scholar
  46. 46.
    Siddiqui A, Rivera-Sanchez S, Castro MR, Acevedo-Torres K, Rane A, Torres-Ramos CA et al (2012) Mitochondrial DNA damage is associated with reduced mitochondrial bioenergetics in Huntington's disease. Free Radic Biol Med 53(7):1478–1488PubMedCrossRefGoogle Scholar
  47. 47.
    Klungland A, Lindahl T (1997) Second pathway for completion of human DNA base excision-repair: reconstitution with purified proteins and requirement for DNase IV (FEN1). EMBO J 16(11):3341–3348PubMedCrossRefGoogle Scholar
  48. 48.
    Kim K, Biade S, Matsumoto Y (1998) Involvement of flap endonuclease 1 in base excision DNA repair. J Biol Chem 273(15):8842–8848PubMedCrossRefGoogle Scholar
  49. 49.
    Podlutsky AJ, Dianova II, Wilson SH, Bohr VA, Dianov GL (2001) DNA synthesis and dRPase activities of polymerase beta are both essential for single-nucleotide patch base excision repair in mammalian cell extracts. Biochemistry (Mosc) 40(3):809–813CrossRefGoogle Scholar
  50. 50.
    Podlutsky AJ, Dianova II, Podust VN, Bohr VA, Dianov GL (2001) Human DNA polymerase beta initiates DNA synthesis during long-patch repair of reduced AP sites in DNA. EMBO J 20(6):1477–1482PubMedCrossRefGoogle Scholar
  51. 51.
    Goula AV, Pearson CE, Della MJ, Trottier Y, Tomkinson AE, Wilson DM III et al (2012) The nucleotide sequence, DNA damage location, and protein stoichiometry influence the base excision repair outcome at CAG/CTG repeats. Biochemistry (Mosc) 51(18):3919–3932CrossRefGoogle Scholar
  52. 52.
    Derevyanko AG, Endutkin AV, Ishchenko AA, Saparbaev MK, Zharkov DO (2012) Initiation of 8-oxoguanine base excision repair within trinucleotide tandem repeats. Biochemistry (Mosc) 77(3):270–279CrossRefGoogle Scholar
  53. 53.
    Jarem DA, Wilson NR, Schermerhorn KM, Delaney S (2011) Incidence and persistence of 8-oxo-7,8-dihydroguanine within a hairpin intermediate exacerbates a toxic oxidation cycle associated with trinucleotide repeat expansion. DNA Repair (Amst) 10(8):887–896CrossRefGoogle Scholar
  54. 54.
    Johri A, Beal MF (2012) Mitochondrial dysfunction in neurodegenerative diseases. J Pharmacol Exp Ther 342(3):619–630PubMedCrossRefGoogle Scholar
  55. 55.
    Damiano M, Galvan L, Deglon N, Brouillet E (2010) Mitochondria in Huntington's disease. Biochim Biophys Acta 1802(1):52–61PubMedCrossRefGoogle Scholar
  56. 56.
    Kim J, Moody JP, Edgerly CK, Bordiuk OL, Cormier K, Smith K et al (2010) Mitochondrial loss, dysfunction and altered dynamics in Huntington's disease. Hum Mol Genet 19(20):3919–3935PubMedCrossRefGoogle Scholar
  57. 57.
    Pena-Diaz J, Jiricny J (2012) Mammalian mismatch repair: error-free or error-prone? Trends Biochem Sci 37(5):206–214PubMedCrossRefGoogle Scholar
  58. 58.
    Fukui K. (2010) DNA mismatch repair in eukaryotes and bacteria. J Nucleic Acids 2010Google Scholar
  59. 59.
    Marti TM, Kunz C, Fleck O (2002) DNA mismatch repair and mutation avoidance pathways. J Cell Physiol 191(1):28–41PubMedCrossRefGoogle Scholar
  60. 60.
    Wilson T, Guerrette S, Fishel R (1999) Dissociation of mismatch recognition and ATPase activity by hMSH2-hMSH3. J Biol Chem 274(31):21659–21664PubMedCrossRefGoogle Scholar
  61. 61.
    Genschel J, Littman SJ, Drummond JT, Modrich P (1998) Isolation of MutSbeta from human cells and comparison of the mismatch repair specificities of MutSbeta and MutSalpha. J Biol Chem 273(31):19895–19901PubMedCrossRefGoogle Scholar
  62. 62.
    Ginetti F, Perego M, Albertini AM, Galizzi A (1996) Bacillus subtilis mutS mutL operon: identification, nucleotide sequence and mutagenesis. Microbiology 142(Pt 8):2021–2029PubMedCrossRefGoogle Scholar
  63. 63.
    Liu B, Nicolaides NC, Markowitz S, Willson JK, Parsons RE, Jen J et al (1995) Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability. Nat Genet 9(1):48–55PubMedCrossRefGoogle Scholar
  64. 64.
    Slean MM, Panigrahi GB, Ranum LP, Pearson CE (2008) Mutagenic roles of DNA "repair" proteins in antibody diversity and disease-associated trinucleotide repeat instability. DNA Repair (Amst) 7(7):1135–1154CrossRefGoogle Scholar
  65. 65.
    Seriola A, Spits C, Simard JP, Hilven P, Haentjens P, Pearson CE et al (2011) Huntington's and myotonic dystrophy hESCs: down-regulated trinucleotide repeat instability and mismatch repair machinery expression upon differentiation. Hum Mol Genet 20(1):176–185PubMedCrossRefGoogle Scholar
  66. 66.
    Bergamini CM, Gambetti S, Dondi A, Cervellati C (2004) Oxygen, reactive oxygen species and tissue damage. Curr Pharm Des 10(14):1611–1626PubMedCrossRefGoogle Scholar
  67. 67.
    Jenner P (2003) Oxidative stress in Parkinson's disease. Ann Neurol 53(Suppl 3):S26–S36PubMedCrossRefGoogle Scholar
  68. 68.
    Sayre LM, Smith MA, Perry G (2001) Chemistry and biochemistry of oxidative stress in neurodegenerative disease. Curr Med Chem 8(7):721–738PubMedCrossRefGoogle Scholar
  69. 69.
    Sayre LM, Perry G, Smith MA (2008) Oxidative stress and neurotoxicity. Chem Res Toxicol 21(1):172–188PubMedCrossRefGoogle Scholar
  70. 70.
    Kennedy L, Evans E, Chen CM, Craven L, Detloff PJ, Ennis M et al (2003) Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis. Hum Mol Genet 12(24):3359–3367PubMedCrossRefGoogle Scholar
  71. 71.
    Kremer B, Goldberg P, Andrew SE, Theilmann J, Telenius H, Zeisler J et al (1994) A worldwide study of the Huntington's disease mutation. The sensitivity and specificity of measuring CAG repeats. N Engl J Med 330(20):1401–1406PubMedCrossRefGoogle Scholar
  72. 72.
    Wheeler VC, Auerbach W, White JK, Srinidhi J, Auerbach A, Ryan A et al (1999) Length-dependent gametic CAG repeat instability in the Huntington's disease knock-in mouse. Hum Mol Genet 8(1):115–122PubMedCrossRefGoogle Scholar
  73. 73.
    Gonitel R, Moffitt H, Sathasivam K, Woodman B, Detloff PJ, Faull RL et al (2008) DNA instability in postmitotic neurons. Proc Natl Acad Sci U S A 105(9):3467–3472PubMedCrossRefGoogle Scholar
  74. 74.
    Li JL, Hayden MR, Almqvist EW, Brinkman RR, Durr A, Dode C et al (2003) A genome scan for modifiers of age at onset in Huntington disease: the HD MAPS study. Am J Hum Genet 73(3):682–687PubMedCrossRefGoogle Scholar
  75. 75.
    Li JL, Hayden MR, Warby SC, Durr A, Morrison PJ, Nance M et al (2006) Genome-wide significance for a modifier of age at neurological onset in Huntington's disease at 6q23-24: the HD MAPS study. BMC Med Genet 7:71PubMedCrossRefGoogle Scholar
  76. 76.
    Wexler NS, Lorimer J, Porter J, Gomez F, Moskowitz C, Shackell E et al (2004) Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset. Proc Natl Acad Sci U S A 101(10):3498–3503PubMedCrossRefGoogle Scholar
  77. 77.
    Kaplan S, Itzkovitz S, Shapiro E (2007) A universal mechanism ties genotype to phenotype in trinucleotide diseases. PLoS Comput Biol 3(11):e235PubMedCrossRefGoogle Scholar
  78. 78.
    Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS et al (1998) Embryonic stem cell lines derived from human blastocysts. Science 282(5391):1145–1147PubMedCrossRefGoogle Scholar
  79. 79.
    McBride JL, Behrstock SP, Chen EY, Jakel RJ, Siegel I, Svendsen CN et al (2004) Human neural stem cell transplants improve motor function in a rat model of Huntington's disease. J Comp Neurol 475(2):211–219PubMedCrossRefGoogle Scholar
  80. 80.
    Okita K, Matsumura Y, Sato Y, Okada A, Morizane A, Okamoto S et al (2011) A more efficient method to generate integration-free human iPS cells. Nat Methods 8(5):409–412PubMedCrossRefGoogle Scholar
  81. 81.
    Okita K, Nakagawa M, Hyenjong H, Ichisaka T, Yamanaka S (2008) Generation of mouse induced pluripotent stem cells without viral vectors. Science 322(5903):949–953PubMedCrossRefGoogle Scholar
  82. 82.
    Fusaki N, Ban H, Nishiyama A, Saeki K, Hasegawa M (2009) Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome. Proc Jpn Acad Ser B Phys Biol Sci 85(8):348–362PubMedCrossRefGoogle Scholar
  83. 83.
    Stadtfeld M, Nagaya M, Utikal J, Weir G, Hochedlinger K (2008) Induced pluripotent stem cells generated without viral integration. Science 322(5903):945–949PubMedCrossRefGoogle Scholar
  84. 84.
    Warren L, Manos PD, Ahfeldt T, Loh YH, Li H, Lau F et al (2010) Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 7(5):618–630PubMedCrossRefGoogle Scholar
  85. 85.
    Kim D, Kim CH, Moon JI, Chung YG, Chang MY, Han BS et al (2009) Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell 4(6):472–476PubMedCrossRefGoogle Scholar
  86. 86.
    Ban H, Nishishita N, Fusaki N, Tabata T, Saeki K, Shikamura M et al (2011) Efficient generation of transgene-free human induced pluripotent stem cells (iPSCs) by temperature-sensitive Sendai virus vectors. Proc Natl Acad Sci U S A 108(34):14234–14239PubMedCrossRefGoogle Scholar
  87. 87.
    The Hd Ipsc Consortium (2012) Induced Pluripotent stem cells from patients with Huntington's disease show CAG-repeat-expansion-associated phenotypes. Cell Stem Cell 11(2):264–278CrossRefGoogle Scholar
  88. 88.
    Chae JI, Kim DW, Lee N, Jeon YJ, Jeon I, Kwon J, et al (2012) Quantitative proteomic analysis of induced pluripotent stem cells derived from a human Huntington's disease patient. Biochem J Google Scholar
  89. 89.
    Jeon I, Lee N, Li JY, Park IH, Park KS, Moon J et al (2012) Neuronal Properties, in vivo effects, and pathology of a Huntington's disease patient-derived induced pluripotent stem cells. Stem Cells 30(9):2054–2062PubMedCrossRefGoogle Scholar
  90. 90.
    Juopperi TA, Kim WR, Chiang CH, Yu H, Margolis RL, Ross CA et al (2012) Astrocytes generated from patient induced pluripotent stem cells recapitulate features of Huntington's disease patient cells. Mol Brain 5(1):17PubMedCrossRefGoogle Scholar
  91. 91.
    Camnasio S, Carri AD, Lombardo A, Grad I, Mariotti C, Castucci A et al (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(1):41–51PubMedCrossRefGoogle Scholar
  92. 92.
    Dunnett SB, Carter RJ, Watts C, Torres EM, Mahal A, Mangiarini L et al (1998) Striatal transplantation in a transgenic mouse model of Huntington's disease. Exp Neurol 154(1):31–40PubMedCrossRefGoogle Scholar
  93. 93.
    Bachoud-Levi AC, Remy P, Nguyen JP, Brugieres P, Lefaucheur JP, Bourdet C et al (2000) Motor and cognitive improvements in patients with Huntington's disease after neural transplantation. Lancet 356(9246):1975–1979PubMedCrossRefGoogle Scholar
  94. 94.
    Bachoud-Levi AC, Gaura V, Brugieres P, Lefaucheur JP, Boisse MF, Maison P et al (2006) Effect of fetal neural transplants in patients with Huntington's disease 6 years after surgery: a long-term follow-up study. Lancet Neurol 5(4):303–309PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of Microbiology, University of OsloOslo University Hospital, RikshospitaletOsloNorway

Personalised recommendations