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The Ubiquitin Proteasome System and Cerebellar Developmental Disease

  • Jerry VriendEmail author
  • Xiaodan Jiao
Chapter
Part of the Contemporary Clinical Neuroscience book series (CCNE)

Abstract

A variety of developmental diseases of the cerebellum are associated with dysregulation of proteins regulated by the ubiquitin proteasome system (UPS). Dysfunction of the UPS is observed in several types of spinocerebellar ataxias associated with polyglutamine accumulation. Spinocerebellar ataxia type 3 is caused by a genetic defect ion the Atxn3 gene, which codes for a deubiquitinase enzyme. Defects in expression of a variety of ubiquitin ligases are associated with Friedreich’s ataxia, ataxia-telangiectasia, and cerebellar hemangioblastoma. Mutations in a number of genes for ubiquitin ligases are risk factors for autism. Subtypes of medulloblastoma are associated with specific defects in proteasome subunits and with deficiencies in components of the APC/C ubiquitin ligase complex regulating the cell cycle. Targeting various components of the UPS system may contribute to a future therapeutic approach which restores protein homeostasis in various cerebellar diseases.

Abbreviations

AIP

Atrophin-interacting protein

A1UP

Ataxin-1 ubiquitin-like interacting protein

APC/C

Anaphase-promoting complex/cyclosome

ASD

Autism spectrum disorder

AT

Ataxia-telangiectasia

ATM

Ataxia-telangiectasia mutated

ATXN1

Ataxin 1

ATXN3

Ataxin 3

CAG

Cytosine-adenine-guanine repeat

CHFR

Checkpoint with forkhead and ring finger domains

DRPLA

Dentatorubropallidoluysian atrophy

DUB

Deubiquitinase

E2

Ubiquitin-conjugating enzyme

E3

Ubiquitin ligase

E1

Ubiquitin-activating enzyme

FRDA

Friedreich’s ataxia

FXN

Frataxin

HIF-1

Hypoxia-inducible factor 1

ITPR

Inositol triphosphate receptor isoform

MB

Medulloblastoma

MJD

Machado-Joseph disease

RNF

Ring finger protein

SCA

Spinocerebellar ataxia

UBR

Ubiquitin protein ligase E3 component N-recognin 4

UPS

Ubiquitin proteasome system

USP

Ubiquitin-specific protease

VEGF

Vascular endothelial growth factor

VHL

von Hippel-Lindau protein

References

  1. 1.
    Hershko A, Ciechanover A. The ubiquitin pathway for the degradation of intracellular proteins. Prog Nucleic Acid Res Mol Biol. 1986;33:19–56. 301PubMedCrossRefGoogle Scholar
  2. 2.
    Reyes-Turcu FE, Ventii KH, Wilkinson KD. Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes. Annu Rev Biochem. 2009;78:363–97.PubMedCrossRefGoogle Scholar
  3. 3.
    Amerik AY, Hochstrasser M. Mechanism and function of deubiquitinating enzymes. Biochim Biophys Acta. 2004;1695(1–3):189–207.PubMedCrossRefGoogle Scholar
  4. 4.
    Komander D, Clague MJ, Urbe S. Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol. 2009;10(8):550–63.PubMedCrossRefGoogle Scholar
  5. 5.
    Livneh I, Cohen-Kaplan V, Cohen-Rosenzweig C, Avni N, Ciechanover A. The life cycle of the 26S proteasome: from birth, through regulation and function, and onto its death. Cell Res. 2016;26(8):869–85.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Fogel BL, Hanson SM, Becker EB. Do mutations in the murine ataxia gene TRPC3 cause cerebellar ataxia in humans? Mov Disord. 2015;30(2):284–6.PubMedCrossRefGoogle Scholar
  7. 7.
    Becker EB. The moonwalker mouse: new insights into TRPC3 function, cerebellar development, and ataxia. Cerebellum. 2014;13(5):628–36.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Tarlac V, Storey E. Role of proteolysis in polyglutamine disorders. J Neurosci Res. 2003;74(3):406–16.PubMedCrossRefGoogle Scholar
  9. 9.
    Orr HT, Chung MY, Banfi S, Kwiatkowski TJ Jr, Servadio A, Beaudet AL, et al. Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet. 1993;4(3):221–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Sanchez I, Balague E, Matilla-Duenas A. Ataxin-1 regulates the cerebellar bioenergetics proteome through the GSK3beta-mTOR pathway which is altered in Spinocerebellar ataxia type 1 (SCA1). Hum Mol Genet. 2016;25(18):4021–40.PubMedCrossRefGoogle Scholar
  11. 11.
    Crespo-Barreto J, Fryer JD, Shaw CA, Orr HT, Zoghbi HY. Partial loss of ataxin-1 function contributes to transcriptional dysregulation in spinocerebellar ataxia type 1 pathogenesis. PLoS Genet. 2010;6(7):e1001021.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Riley BE, Xu Y, Zoghbi HY, Orr HT. The effects of the polyglutamine repeat protein ataxin-1 on the UbL-UBA protein A1Up. J Biol Chem. 2004;279(40):42290–301.PubMedCrossRefGoogle Scholar
  13. 13.
    Su V, Lau AF. Ubiquitin-like and ubiquitin-associated domain proteins: significance in proteasomal degradation. Cell Mol Life Sci. 2009;66(17):2819–33.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Al-Ramahi I, Lam YC, Chen HK, de Gouyon B, Zhang M, Perez AM, et al. CHIP protects from the neurotoxicity of expanded and wild-type ataxin-1 and promotes their ubiquitination and degradation. J Biol Chem. 2006;281(36):26714–24.PubMedCrossRefGoogle Scholar
  15. 15.
    Williams AJ, Knutson TM, Colomer Gould VF, Paulson HL. In vivo suppression of polyglutamine neurotoxicity by C-terminus of Hsp70-interacting protein (CHIP) supports an aggregation model of pathogenesis. Neurobiol Dis. 2009;33(3):342–53.PubMedCrossRefGoogle Scholar
  16. 16.
    Preiksaitiene E, Krasovskaja N, Utkus A, Kasnauskiene J, Meskiene R, Paulauskiene I, et al. R368X mutation in MID1 among recurrent mutations in patients with X-linked Opitz G/BBB syndrome. Clin Dysmorphol. 2015;24(1):7–12.PubMedCrossRefGoogle Scholar
  17. 17.
    De Falco F, Cainarca S, Andolfi G, Ferrentino R, Berti C, Rodriguez Criado G, et al. X-linked Opitz syndrome: novel mutations in the MID1 gene and redefinition of the clinical spectrum. Am J Med Genet A. 2003;120A(2):222–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Lastres-Becker I, Rub U, Auburger G. Spinocerebellar ataxia 2 (SCA2). Cerebellum. 2008;7(2):115–24.PubMedCrossRefGoogle Scholar
  19. 19.
    Li PP, Sun X, Xia G, Arbez N, Paul S, Zhu S, et al. ATXN2-AS, a gene antisense to ATXN2, is associated with spinocerebellar ataxia type 2 and amyotrophic lateral sclerosis. Ann Neurol. 2016;80(4):600–15.PubMedCrossRefGoogle Scholar
  20. 20.
    Pulst SM. Degenerative ataxias, from genes to therapies: the 2015 Cotzias lecture. Neurology. 2016;86(24):2284–90.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Nakano KK, Dawson DM, Spence A. Machado disease. A hereditary ataxia in Portuguese emigrants to Massachusetts. Neurology. 1972;22(1):49–55.PubMedCrossRefGoogle Scholar
  22. 22.
    Matilla T, McCall A, Subramony SH, Zoghbi HY. Molecular and clinical correlations in spinocerebellar ataxia type 3 and Machado-Joseph disease. Ann Neurol. 1995;38(1):68–72.PubMedCrossRefGoogle Scholar
  23. 23.
    Bettencourt C, Lima M. Machado-Joseph disease: from first descriptions to new perspectives. Orphanet J Rare Dis. 2011;6:35.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Seidel K, Siswanto S, Fredrich M, Bouzrou M, Brunt ER, van Leeuwen FW, et al. Polyglutamine aggregation in Huntington’s disease and spinocerebellar ataxia type 3: similar mechanisms in aggregate formation. Neuropathol Appl Neurobiol. 2016;42(2):153–66.PubMedCrossRefGoogle Scholar
  25. 25.
    Kawaguchi Y, Okamoto T, Taniwaki M, Aizawa M, Inoue M, Katayama S, et al. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet. 1994;8(3):221–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Limprasert P, Nouri N, Heyman RA, Nopparatana C, Kamonsilp M, Deininger PL, et al. Analysis of CAG repeat of the Machado-Joseph gene in human, chimpanzee and monkey populations: a variant nucleotide is associated with the number of CAG repeats. Hum Mol Genet. 1996;5(2):207–13.PubMedCrossRefGoogle Scholar
  27. 27.
    Riess O, Rub U, Pastore A, Bauer P, Schols L. SCA3: neurological features, pathogenesis and animal models. Cerebellum. 2008;7(2):125–37.PubMedCrossRefGoogle Scholar
  28. 28.
    Matos CA, de Macedo-Ribeiro S, Carvalho AL. Polyglutamine diseases: the special case of ataxin-3 and Machado-Joseph disease. Prog Neurobiol. 2011;95(1):26–48.PubMedCrossRefGoogle Scholar
  29. 29.
    Koch P, Breuer P, Peitz M, Jungverdorben J, Kesavan J, Poppe D, et al. Excitation-induced ataxin-3 aggregation in neurons from patients with Machado-Joseph disease. Nature. 2011;480(7378):543–6.PubMedCrossRefGoogle Scholar
  30. 30.
    Zoghbi HY, Orr HT. Glutamine repeats and neurodegeneration. Annu Rev Neurosci. 2000;23:217–47.PubMedCrossRefGoogle Scholar
  31. 31.
    Schols L, Reimold M, Seidel K, Globas C, Brockmann K, Hauser TK, et al. No parkinsonism in SCA2 and SCA3 despite severe neurodegeneration of the dopaminergic substantia nigra. Brain. 2015;138(Pt 11):3316–26.PubMedCrossRefGoogle Scholar
  32. 32.
    Jana NR, Nukina N. Recent advances in understanding the pathogenesis of polyglutamine diseases: involvement of molecular chaperones and ubiquitin-proteasome pathway. J Chem Neuroanat. 2003;26(2):95–101.PubMedCrossRefGoogle Scholar
  33. 33.
    Schmidt T, Lindenberg KS, Krebs A, Schols L, Laccone F, Herms J, et al. Protein surveillance machinery in brains with spinocerebellar ataxia type 3: redistribution and differential recruitment of 26S proteasome subunits and chaperones to neuronal intranuclear inclusions. Ann Neurol. 2002;51(3):302–10.PubMedCrossRefGoogle Scholar
  34. 34.
    Burnett B, Li F, Pittman RN. The polyglutamine neurodegenerative protein ataxin-3 binds polyubiquitylated proteins and has ubiquitin protease activity. Hum Mol Genet. 2003;12(23):3195–205.PubMedCrossRefGoogle Scholar
  35. 35.
    Winborn BJ, Travis SM, Todi SV, Scaglione KM, Xu P, Williams AJ, et al. The deubiquitinating enzyme ataxin-3, a polyglutamine disease protein, edits Lys63 linkages in mixed linkage ubiquitin chains. J Biol Chem. 2008;283(39):26436–43.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Miles RR, Crockett DK, Lim MS, Elenitoba-Johnson KS. Analysis of BCL6-interacting proteins by tandem mass spectrometry. Mol Cell Proteomics. 2005;4(12):1898–909.PubMedCrossRefGoogle Scholar
  37. 37.
    Depondt C, Donatello S, Simonis N, Rai M, van Heurck R, Abramowicz M, et al. Autosomal recessive cerebellar ataxia of adult onset due to STUB1 mutations. Neurology. 2014;82(19):1749–50.PubMedCrossRefGoogle Scholar
  38. 38.
    Durcan TM, Fon EA. Ataxin-3 and its e3 partners: implications for machado-joseph disease. Front Neurol. 2013;4:46.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Todi SV, Winborn BJ, Scaglione KM, Blount JR, Travis SM, Paulson HL. Ubiquitination directly enhances activity of the deubiquitinating enzyme ataxin-3. EMBO J. 2009;28(4):372–82.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Todi SV, Scaglione KM, Blount JR, Basrur V, Conlon KP, Pastore A, et al. Activity and cellular functions of the deubiquitinating enzyme and polyglutamine disease protein ataxin-3 are regulated by ubiquitination at lysine 117. J Biol Chem. 2010;285(50):39303–13.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Chai Y, Koppenhafer SL, Shoesmith SJ, Perez MK, Paulson HL. Evidence for proteasome involvement in polyglutamine disease: localization to nuclear inclusions in SCA3/MJD and suppression of polyglutamine aggregation in vitro. Hum Mol Genet. 1999;8(4):673–82.PubMedCrossRefGoogle Scholar
  42. 42.
    Cemal CK, Carroll CJ, Lawrence L, Lowrie MB, Ruddle P, Al-Mahdawi S, et al. YAC transgenic mice carrying pathological alleles of the MJD1 locus exhibit a mild and slowly progressive cerebellar deficit. Hum Mol Genet. 2002;11(9):1075–94.PubMedCrossRefGoogle Scholar
  43. 43.
    Alves S, Nascimento-Ferreira I, Dufour N, Hassig R, Auregan G, Nobrega C, et al. Silencing ataxin-3 mitigates degeneration in a rat model of Machado-Joseph disease: no role for wild-type ataxin-3? Hum Mol Genet. 2010;19(12):2380–94.PubMedCrossRefGoogle Scholar
  44. 44.
    Dick KA, Ikeda Y, Day JW, Ranum LP. Spinocerebellar ataxia type 5. Handb Clin Neurol. 2012;103:451–9.PubMedCrossRefGoogle Scholar
  45. 45.
    Machnicka B, Grochowalska R, Boguslawska DM, Sikorski AF, Lecomte MC. Spectrin-based skeleton as an actor in cell signaling. Cell Mol Life Sci. 2012;69(2):191–201.PubMedCrossRefGoogle Scholar
  46. 46.
    Chang TL, Cubillos FF, Kakhniashvili DG, Goodman SR. Ankyrin is a target of spectrin’s E2/E3 ubiquitin-conjugating/ligating activity. Cell Mol Biol (Noisy-le-Grand). 2004;50(1):59–66.Google Scholar
  47. 47.
    Hsu YJ, Goodman SR. Spectrin and ubiquitination: a review. Cell Mol Biol (Noisy-le-grand). 2005;Suppl 51:OL801–7.Google Scholar
  48. 48.
    Goodman SR, Petrofes Chapa R, Zimmer WE. Spectrin’s chimeric E2/E3 enzymatic activity. Exp Biol Med (Maywood). 2015;240(8):1039–49.CrossRefGoogle Scholar
  49. 49.
    Zhuchenko O, Bailey J, Bonnen P, Ashizawa T, Stockton DW, Amos C, et al. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat Genet. 1997;15(1):62–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Mohan RD, Abmayr SM, Workman JL. Pulling complexes out of complex diseases: spinocerebellar ataxia 7. Rare Dis. 2014;2:e28859.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Morgan MT, Haj-Yahya M, Ringel AE, Bandi P, Brik A, Wolberger C. Structural basis for histone H2B deubiquitination by the SAGA DUB module. Science. 2016;351(6274):725–8.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Yang H, Liu S, He WT, Zhao J, Jiang LL, Hu HY. Aggregation of Polyglutamine-expanded Ataxin 7 protein specifically sequesters ubiquitin-specific protease 22 and deteriorates its deubiquitinating function in the Spt-Ada-Gcn5-Acetyltransferase (SAGA) complex. J Biol Chem. 2015;290(36):21996–2004.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Li ZH, Yu Y, Du C, Fu H, Wang J, Tian Y. RNA interference-mediated USP22 gene silencing promotes human brain glioma apoptosis and induces cell cycle arrest. Oncol Lett. 2013;5(4):1290–4.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Moseley ML, Zu T, Ikeda Y, Gao W, Mosemiller AK, Daughters RS, et al. Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8. Nat Genet. 2006;38(7):758–69.PubMedCrossRefGoogle Scholar
  55. 55.
    Nemes JP, Benzow KA, Moseley ML, Ranum LP, Koob MD. The SCA8 transcript is an antisense RNA to a brain-specific transcript encoding a novel actin-binding protein (KLHL1). Hum Mol Genet. 2000;9(10):1543–51.PubMedCrossRefGoogle Scholar
  56. 56.
    Storey E. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, et al., editors. Spinocerebellar ataxia type 15. Seattle: GeneReviews(R); 1993.Google Scholar
  57. 57.
    Conroy J, McGettigan P, Murphy R, Webb D, Murphy SM, McCoy B, et al. A novel locus for episodic ataxia:UBR4 the likely candidate. Eur J Hum Genet. 2014;22(4):505–10.PubMedCrossRefGoogle Scholar
  58. 58.
    Sermwittayawong D, Tan S. SAGA binds TBP via its Spt8 subunit in competition with DNA: implications for TBP recruitment. EMBO J. 2006;25(16):3791–800.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Wang L, Dent SY. Functions of SAGA in development and disease. Epigenomics. 2014;6(3):329–39.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Weake VM, Workman JL. SAGA function in tissue-specific gene expression. Trends Cell Biol. 2012;22(4):177–84.PubMedCrossRefGoogle Scholar
  61. 61.
    Lee YC, Durr A, Majczenko K, Huang YH, Liu YC, Lien CC, et al. Mutations in KCND3 cause spinocerebellar ataxia type 22. Ann Neurol. 2012;72(6):859–69.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Lehmann G, Udasin RG, Ciechanover A. On the linkage between the ubiquitin-proteasome system and the mitochondria. Biochem Biophys Res Commun. 2016;473(1):80–6.PubMedCrossRefGoogle Scholar
  63. 63.
    Shi Y, Wang J, Li JD, Ren H, Guan W, He M, et al. Identification of CHIP as a novel causative gene for autosomal recessive cerebellar ataxia. PLoS One. 2013;8(12):e81884.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Shi CH, Schisler JC, Rubel CE, Tan S, Song B, McDonough H, et al. Ataxia and hypogonadism caused by the loss of ubiquitin ligase activity of the U box protein CHIP. Hum Mol Genet. 2014;23(4):1013–24.PubMedCrossRefGoogle Scholar
  65. 65.
    Ronnebaum SM, Patterson C, Schisler JC. Emerging evidence of coding mutations in the ubiquitin-proteasome system associated with cerebellar ataxias. Hum Genome Var. 2014;1:14018.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Yuasa T. Hereditary dentatorubro-pallidoluysian atrophy (DRPLA): clinical studies on 45 cases. Nihon Rinsho Jpn J Clin Med. 1993;51(11):3016–23.Google Scholar
  67. 67.
    Matilla-Duenas A. Machado-Joseph disease and other rare spinocerebellar ataxias. Adv Exp Med Biol. 2012;724:172–88.PubMedCrossRefGoogle Scholar
  68. 68.
    Kanazawa I. Dentatorubral-pallidoluysian atrophy or Naito-Oyanagi disease. Neurogenetics. 1998;2(1):1–17.PubMedCrossRefGoogle Scholar
  69. 69.
    Yamada M, Shimohata M, Sato T, Tsuji S, Takahashi H. Polyglutamine disease: recent advances in the neuropathology of dentatorubral-pallidoluysian atrophy. Neuropathology. 2006;26(4):346–51.PubMedCrossRefGoogle Scholar
  70. 70.
    Tsuji S. Dentatorubral-pallidoluysian atrophy. Handb Clin Neurol. 2012;103:587–94.PubMedCrossRefGoogle Scholar
  71. 71.
    Fan HC, Ho LI, Chi CS, Chen SJ, Peng GS, Chan TM, et al. Polyglutamine (PolyQ) diseases: genetics to treatments. Cell Transplant. 2014;23(4–5):441–58.PubMedCrossRefGoogle Scholar
  72. 72.
    Suzuki Y, Yazawa I. Pathological accumulation of atrophin-1 in dentatorubralpallidoluysian atrophy. Int J Clin Exp Pathol. 2011;4(4):378–84.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Wood JD, Yuan J, Margolis RL, Colomer V, Duan K, Kushi J, et al. Atrophin-1, the DRPLA gene product, interacts with two families of WW domain-containing proteins. Mol Cell Neurosci. 1998;11(3):149–60.PubMedCrossRefGoogle Scholar
  74. 74.
    Feng L, Guedes S, Wang T. Atrophin-1-interacting protein 4/human Itch is a ubiquitin E3 ligase for human enhancer of filamentation 1 in transforming growth factor-beta signaling pathways. J Biol Chem. 2004;279(28):29681–90.PubMedCrossRefGoogle Scholar
  75. 75.
    Qiu L, Joazeiro C, Fang N, Wang HY, Elly C, Altman Y, et al. Recognition and ubiquitination of notch by Itch, a hect-type E3 ubiquitin ligase. J Biol Chem. 2000;275(46):35734–7.PubMedCrossRefGoogle Scholar
  76. 76.
    Fang D, Elly C, Gao B, Fang N, Altman Y, Joazeiro C, et al. Dysregulation of T lymphocyte function in itchy mice: a role for Itch in TH2 differentiation. Nat Immunol. 2002;3(3):281–7.PubMedCrossRefGoogle Scholar
  77. 77.
    Koeppen AH. Friedreich’s ataxia: pathology, pathogenesis, and molecular genetics. J Neurol Sci. 2011;303(1–2):1–12.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Chamberlain S, Shaw J, Rowland A, Wallis J, South S, Nakamura Y, et al. Mapping of mutation causing Friedreich’s ataxia to human chromosome 9. Nature. 1988;334(6179):248–50.PubMedCrossRefGoogle Scholar
  79. 79.
    Campuzano V, Montermini L, Molto MD, Pianese L, Cossee M, Cavalcanti F, et al. Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science. 1996;271(5254):1423–7.PubMedCrossRefGoogle Scholar
  80. 80.
    Busi MV, Gomez-Casati DF. Exploring frataxin function. IUBMB Life. 2012;64(1):56–63.PubMedCrossRefGoogle Scholar
  81. 81.
    Patel PI, Isaya G. Friedreich ataxia: from GAA triplet-repeat expansion to frataxin deficiency. Am J Hum Genet. 2001;69(1):15–24.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Fleming J, Spinoulas A, Zheng M, Cunningham SC, Ginn SL, McQuilty RC, et al. Partial correction of sensitivity to oxidant stress in Friedreich ataxia patient fibroblasts by frataxin-encoding adeno-associated virus and lentivirus vectors. Hum Gene Ther. 2005;16(8):947–56.PubMedCrossRefGoogle Scholar
  83. 83.
    Libri V, Yandim C, Athanasopoulos S, Loyse N, Natisvili T, Law PP, et al. Epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich’s ataxia: an exploratory, open-label, dose-escalation study. Lancet. 2014;384(9942):504–13.PubMedCrossRefGoogle Scholar
  84. 84.
    Rufini A, Fortuni S, Arcuri G, Condo I, Serio D, Incani O, et al. Preventing the ubiquitin-proteasome-dependent degradation of frataxin, the protein defective in Friedreich’s ataxia. Hum Mol Genet. 2011;20(7):1253–61.PubMedCrossRefGoogle Scholar
  85. 85.
    Rufini A, Cavallo F, Condo I, Fortuni S, De Martino G, Incani O, et al. Highly specific ubiquitin-competing molecules effectively promote frataxin accumulation and partially rescue the aconitase defect in Friedreich ataxia cells. Neurobiol Dis. 2015;75:91–9.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Choi KD, Choi JH. Episodic ataxias: clinical and genetic features. J Mov Disord. 2016;9(3):129–35.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Tasaki T, Mulder LC, Iwamatsu A, Lee MJ, Davydov IV, Varshavsky A, et al. A family of mammalian E3 ubiquitin ligases that contain the UBR box motif and recognize N-degrons. Mol Cell Biol. 2005;25(16):7120–36.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Parsons K, Nakatani Y, Nguyen MD. p600/UBR4 in the central nervous system. Cell Mol Life Sci: CMLS. 2015;72(6):1149–60.PubMedCrossRefGoogle Scholar
  89. 89.
    Brandt T, Strupp M. Episodic ataxia type 1 and 2 (familial periodic ataxia/vertigo). Audiol Neurootol. 1997;2(6):373–83.PubMedCrossRefGoogle Scholar
  90. 90.
    Pelc S, Vis H. Familia ataxia with ocular telangiectasis (D. Louis-bar syndrome). Acta Neurol Belg. 1960;60:905–22.Google Scholar
  91. 91.
    Subba RK. Mechanisms of disease: DNA repair defects and neurological disease. Nat Clin Pract Neurol. 2007;3(3):162–72.CrossRefGoogle Scholar
  92. 92.
    Lee JH, Paull TT. Activation and regulation of ATM kinase activity in response to DNA double-strand breaks. Oncogene. 2007;26(56):7741–8.PubMedCrossRefGoogle Scholar
  93. 93.
    Shiloh Y, Ziv Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Biol. 2013;14(4):197–210.PubMedCrossRefGoogle Scholar
  94. 94.
    Levy-Barda A, Lerenthal Y, Davis AJ, Chung YM, Essers J, Shao Z, et al. Involvement of the nuclear proteasome activator PA28gamma in the cellular response to DNA double-strand breaks. Cell Cycle. 2011;10(24):4300–10.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Slater A, Moore NR, Huson SM. The natural history of cerebellar hemangioblastomas in von Hippel-Lindau disease. AJNR Am J Neuroradiol. 2003;24(8):1570–4.PubMedGoogle Scholar
  96. 96.
    Richard S, Campello C, Taillandier L, Parker F, Resche F. Haemangioblastoma of the central nervous system in von Hippel-Lindau disease. French VHL study group. J Intern Med. 1998;243(6):547–53.PubMedCrossRefGoogle Scholar
  97. 97.
    Glasker S, Li J, Xia JB, Okamoto H, Zeng W, Lonser RR, et al. Hemangioblastomas share protein expression with embryonal hemangioblast progenitor cell. Cancer Res. 2006;66(8):4167–72.PubMedCrossRefGoogle Scholar
  98. 98.
    Maher ER, Neumann HP, Richard S. Von Hippel-Lindau disease: a clinical and scientific review. Eur J Hum Genet. 2011;19(6):617–23.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Iwai K, Yamanaka K, Kamura T, Minato N, Conaway RC, Conaway JW, et al. Identification of the von Hippel-lindau tumor-suppressor protein as part of an active E3 ubiquitin ligase complex. Proc Natl Acad Sci U S A. 1999;96(22):12436–41.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Semenza GL. HIF-1 and mechanisms of hypoxia sensing. Curr Opin Cell Biol. 2001;13(2):167–71.PubMedCrossRefGoogle Scholar
  101. 101.
    Shih SC, Claffey KP. Hypoxia-mediated regulation of gene expression in mammalian cells. Int J Exp Pathol. 1998;79(6):347–57.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Min JH, Yang H, Ivan M, Gertler F, Kaelin WG Jr, Pavletich NP. Structure of an HIF-1alpha -pVHL complex: hydroxyproline recognition in signaling. Science. 2002;296(5574):1886–9.PubMedCrossRefGoogle Scholar
  103. 103.
    Donovan AP, Basson MA. The neuroanatomy of autism – a developmental perspective. J Anat. 2017;230(1):4–15.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Hashimoto T, Tayama M, Murakawa K, Yoshimoto T, Miyazaki M, Harada M, et al. Development of the brainstem and cerebellum in autistic patients. J Autism Dev Disord. 1995;25(1):1–18.PubMedCrossRefGoogle Scholar
  105. 105.
    Louros SR, Osterweil EK. Perturbed proteostasis in autism spectrum disorders. J Neurochem. 2016;139(6):1081–92.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Baron CA, Tepper CG, Liu SY, Davis RR, Wang NJ, Schanen NC, et al. Genomic and functional profiling of duplicated chromosome 15 cell lines reveal regulatory alterations in UBE3A-associated ubiquitin-proteasome pathway processes. Hum Mol Genet. 2006;15(6):853–69.PubMedCrossRefGoogle Scholar
  107. 107.
    Buiting K, Williams C, Horsthemke B. Angelman syndrome – insights into a rare neurogenetic disorder. Nat Rev Neurol. 2016;12(10):584–93.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Kishino T, Wagstaff J. Genomic organization of the UBE3A/E6-AP gene and related pseudogenes. Genomics. 1998;47(1):101–7.PubMedCrossRefGoogle Scholar
  109. 109.
    Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 2012;123(4):465–72.PubMedCrossRefGoogle Scholar
  110. 110.
    Vriend J, Ghavami S, Marzban H. The role of the ubiquitin proteasome system in cerebellar development and medulloblastoma. Mol Brain. 2015;8(1):64.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Thompson MC, Fuller C, Hogg TL, Dalton J, Finkelstein D, Lau CC, et al. Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. J Clin Oncol: Off J Am Soc Clin Oncol. 2006;24(12):1924–31.CrossRefGoogle Scholar
  112. 112.
    Vriend J, Marzban H. The ubiquitin-proteasome system and chromosome 17 in cerebellar granule cells and medulloblastoma subgroups. Cellular Mol Life Sci: CMLS 2017;74(3): 449–67.PubMedCrossRefGoogle Scholar
  113. 113.
    Penas C, Govek EE, Fang Y, Ramachandran V, Daniel M, Wang W, et al. Casein kinase 1delta is an APC/C(Cdh1) substrate that regulates cerebellar granule cell neurogenesis. Cell Rep. 2015;11(2):249–60.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Wiebusch L, Bach M, Uecker R, Hagemeier C. Human cytomegalovirus inactivates the G0/G1-APC/C ubiquitin ligase by Cdh1 dissociation. Cell Cycle. 2005;4(10):1435–9.PubMedCrossRefGoogle Scholar
  115. 115.
    Hawkins C, Croul S. Viruses and human brain tumors: cytomegalovirus enters the fray. J Clin Invest. 2011;121(10):3831–3.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Baryawno N, Rahbar A, Wolmer-Solberg N, Taher C, Odeberg J, Darabi A, et al. Detection of human cytomegalovirus in medulloblastomas reveals a potential therapeutic target. J Clin Invest. 2011;121(10):4043–55.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health SciencesUniversity of ManitobaWinnipegCanada

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