Top

Published in:

01-03-2013 | Review

Evolving neurobiology of tuberous sclerosis complex

Author: Peter B. Crino

Published in: Acta Neuropathologica | Issue 3/2013

Abstract

Over the past decade, there have been numerous advances in our understanding of the molecular pathogenesis of tuberous sclerosis complex (TSC). Following the identification of the TSC1 and TSC2 genes, a link to regulatory control of the mammalian target of rapamycin (mTOR) signaling pathway has paved the way for new therapeutic interventions, and now even approved therapies for TSC. Gene identification has permitted establishment of cell lines and conditional knockout mouse strains to assay how abnormalities in brain structure lead to enhanced excitability, seizures, cognitive disabilities, and other neuropsychological disorders in TSC. Furthermore, work in in vitro systems and analysis of rodent models and human tissue has allowed investigators to study how brain lesions form in TSC. Evolving questions over the next decade include understanding the high clinical variability of TSC, defining why there is a lack of clear genotype–phenotype correlations, and identifying biomarkers for prognosis and stratification. The study of TSC has in many ways reflected a paradigm “bench-to-bedside” success story that serves as a model of many other neurological disorders.

Anderl S, Freeland M, Kwiatkowski DJ, Goto J (2011) Therapeutic value of prenatal rapamycin treatment in a mouse brain model of tuberous sclerosis complex. Hum Mol Genet 20:4597–4604PubMedCrossRef

Au KS, Williams AT, Roach ES et al (2007) Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States. Genet Med. 9:88–100PubMedCrossRef

Baybis M, Yu J, Lee A, Golden JA, Weiner H, McKhann G II, Aronica E, Crino PB (2004) Activation of the mTOR cascade distinguishes cortical tubers from focal cortical dysplasia. Ann Neurol 56:478–487PubMedCrossRef

Bissler JJ, McCormack FX, Young LR et al (2008) Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 358:140–151PubMedCrossRef

Boer K, Troost D, Timmermans W, Gorter JA, Spliet WG, Nellist M, Jansen F, Aronica E (2008) Cellular localization of metabotropic glutamate receptors in cortical tubers and subependymal giant cell tumors of tuberous sclerosis complex. Neuroscience 156:203–215PubMedCrossRef

Boer K, Crino PB, Gorter JA, Nellist M, Jansen FE, Spliet WG, van Rijen PC, Wittink FR, Breit TM, Troost D, Wadman WJ, Aronica E (2010) Gene expression analysis of tuberous sclerosis complex cortical tubers reveals increased expression of adhesion and inflammatory factors. Brain Pathol 20:704–719PubMedCrossRef

Boer K, Troost D, Jansen F, Nellist M, van den Ouweland AM, Geurts JJ, Spliet WG, Crino P, Aronica E (2008) Clinicopathological and immunohistochemical findings in an autopsy case of tuberous sclerosis complex. Neuropathology 28:577–590PubMed

Carson RP, Van Nielen DL, Winzenburger PA, Ess KC (2012) Neuronal and glia abnormalities in Tsc1-deficient forebrain and partial rescue by rapamycin. Neurobiol Dis 45:369–380PubMedCrossRef

Cepeda C, André VM, Yamazaki I, Hauptman JS, Chen JY, Vinters HV et al (2010) Comparative study of cellular and synaptic abnormalities in brain tissue samples from pediatric tuberous sclerosis complex and cortical dysplasia type II. Epilepsia 51(Suppl 3):160–165PubMedCrossRef

10.

Chan JA, Zhang H, Roberts PS et al (2004) Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: biallelic inactivation of TSC1 or TSC2 leads to mTOR activation. J Neuropathol Exp Neurol 63:1236–1242PubMed

11.

Choi YJ, Di Nardo A, Kramvis I et al (2008) Tuberous sclerosis complex proteins control axon formation. Genes Dev 22:2485–2495PubMedCrossRef

12.

Crino PB, Trojanowski JQ, Dichter MA, Eberwine J (1996) Embryonic neuronal markers in tuberous sclerosis: single-cell molecular pathology. Proc Natl Acad Sci USA. 93(24):14152–14157PubMedCrossRef

13.

Crino PB, Nathanson KL, Henske EP (2006) The tuberous sclerosis complex. N Engl J Med 355:1345–1356PubMedCrossRef

14.

Crino PB, Aronica E, Baltuch G, Nathanson KL (2010) Biallelic TSC gene inactivation in tuberous sclerosis complex. Neurology 74:1716–1723PubMedCrossRef

15.

Dabora SL, Jozwiak S, Franz DN et al (2001) Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. Am J Hum Genet 68:64–80PubMedCrossRef

16.

Dabora SL, Franz DN, Ashwal S et al (2011) Multicenter phase 2 trial of sirolimus for tuberous sclerosis: kidney angiomyolipomas and other tumors regress and VEGF-D levels decrease. PLoS ONE 6:e23379PubMedCrossRef

17.

Davies DM, Johnson SR, Tattersfield AE et al (2008) Sirolimus therapy in tuberous sclerosis or sporadic lymphangioleiomyomatosis. N Engl J Med 358:200–203PubMedCrossRef

18.

Davies DM, de Vries PJ, Johnson SR et al (2011) Sirolimus therapy for angiomyolipoma in tuberous sclerosis and sporadic lymphangioleiomyomatosis: a phase 2 trial. Clin Cancer Res 17:4071–4081PubMedCrossRef

19.

Dibble CC, Elis W, Menon S, Qin W, Klekota J, Asara JM, Finan PM, Kwiatkowski DJ, Murphy LO, Manning BD (2012) TBC1D7 Is a third subunit of the TSC1–TSC2 complex upstream of mTORC1. Mol Cell 47:535–546PubMedCrossRef

20.

Ehninger D, Han S, Shilyansky C et al (2008) Reversal of learning deficits in a Tsc2+/− mouse model of tuberous sclerosis. Nat Med 14:843–848PubMedCrossRef

21.

Ehninger D, Silva AJ (2010) Rapamycin for treating tuberous sclerosis and autism spectrum disorders. Trends Mol Med. 17:78–87PubMedCrossRef

22.

Ellisen LW (2005) Growth control under stress: mTOR regulation through the REDD1-TSC pathway. Cell Cycle 4:1500–1502PubMedCrossRef

23.

European Tuberous Sclerosis Consortium (1993) Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 75:1305–1315CrossRef

24.

Feliciano DM, Su T, Lopez J, Platel JC, Bordey A (2011) Single-cell Tsc1 knockout during corticogenesis generates tuber-like lesions and reduces seizure threshold in mice. J Clin Invest 121:1596–1607PubMedCrossRef

25.

Fukutani Y, Yasuda M, Saitoh C, Kyoya S, Kobayashi K, Miyazu K, Nakamura I (1992) An autopsy case of tuberous sclerosis. Histological and immunohistochemical study. Histol Histopathol 7:709–714PubMed

26.

Gallagher A, Grant EP, Madan N et al (2010) MRI findings reveal three different types of tubers in patients with tuberous sclerosis complex. J Neurol 257:1373–1381PubMedCrossRef

27.

Gao X, Pan D (2001) TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth. Genes Dev 15:1383–1392PubMedCrossRef

28.

Goorden SM, van Woerden GM, van der Weerd L, Cheadle JP, Elgersma Y (2007) Cognitive deficits in Tsc1+/− mice in the absence of cerebral lesions and seizures. Ann Neurol 62:648–655PubMedCrossRef

29.

Goto J, Talos DM, Klein P et al (2011) Regulable neural progenitor-specific Tsc1 loss yields giant cells with organellar dysfunction in a model of tuberous sclerosis complex. Proc Natl Acad Sci USA. 108(45):E1070–E1079PubMedCrossRef

30.

Grajkowska W, Kotulska K, Jurkiewicz E, Roszkowski M, Daszkiewicz P, Jóźwiak S, Matyja E (2011) Subependymal giant cell astrocytomas with atypical histological features mimicking malignant gliomas. Folia Neuropathol 49:39–46PubMed

31.

Green AJ, Smith M, Yates JR (1994) Loss of heterozygosity on chromosome 16p13.3 in hamartomas from tuberous sclerosis patients. Nat Genet 6:193–196PubMedCrossRef

32.

Henske EP, Scheithauer BW, Short MP et al (1996) Allelic loss is frequent in tuberous sclerosis kidney lesions but rare in brain lesions. Am J Hum Genet 59:400–406PubMed

33.

Henske EP, Wessner LL, Golden J et al (1997) Loss of tuberin in both subependymal giant cell astrocytomas and angiomyolipomas supports a two-hit model for the pathogenesis of tuberous sclerosis tumors. Am J Pathol 151:1639–1647PubMed

34.

Hirose T, Scheithauer BW, Lopes MB, Gerber HA, Altermatt HJ, Hukee MJ, VandenBerg SR, Charlesworth JC (1995) Tuber and subependymal giant cell astrocytoma associated with tuberous sclerosis: an immunohistochemical, ultrastructural, and immunoelectron and microscopic study. Acta Neuropath 90:387–399PubMedCrossRef

35.

Hsu PP, Kang SA, Rameseder J et al (2011) The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science 332:1317–1322PubMedCrossRef

36.

Huang J, Manning BD (2008) The TSC1–TSC2 complex: a molecular switchboard controlling cell growth. Biochem J 412:179–190PubMedCrossRef

37.

Huang J, Wu S, Wu CL, Manning BD (2009) Signaling events downstream of mammalian target of rapamycin complex 2 are attenuated in cells and tumors deficient for the tuberous sclerosis complex tumor suppressors. Cancer Res 69:6107–6114PubMedCrossRef

38.

Jacinto E, Loewith R, Schmidt A et al (2004) Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 6:1122–1128PubMedCrossRef

39.

Jansen LA, Uhlmann EJ, Crino PB, Gutmann DH, Wong M (2005) Epileptogenesis and reduced inward rectifier potassium current in tuberous sclerosis complex-1 deficient astrocytes. Epilepsia 46:1871–1880PubMedCrossRef

40.

Jones AC, Daniells CE, Snell RG et al (1997) Molecular genetic and phenotypic analysis reveals differences between TSC1 and TSC2 associated familial and sporadic tuberous sclerosis. Hum Mol Genet 6:2155–2161PubMedCrossRef

41.

Jones AC, Shyamsundar MM, Thomas MW et al (1999) Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis. Am J Hum Genet 64:1305–1315PubMedCrossRef

42.

Kobayashi T, Minowa O, Sugitani Y et al (2001) A germ-line Tsc1 mutation causes tumor development and embryonic lethality that are similar, but not identical to, those caused by Tsc2 mutation in mice. Proc Natl Acad Sci USA. 98:8762–8767PubMedCrossRef

43.

Krueger DA, Care MM, Holland K et al (2010) Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 363:1801–1811PubMedCrossRef

44.

Kyin R, Hua Y, Baybis M, Scheithauer B, Kolson D, Uhlmann E, Gutmann D, Crino PB (2001) Differential cellular expression of neurotrophins in cortical tubers of the tuberous sclerosis complex. Am J Pathol 159:1541–1554PubMedCrossRef

45.

Lamb RF, Roy C, Diefenbach TJ et al (2000) The TSC1 tumour suppressor hamartin regulates cell adhesion through ERM proteins and the GTPase Rho. Nat Cell Biol 2:281–287PubMedCrossRef

46.

Larson Y, Liu J, Stevens PD et al (2010) Tuberous sclerosis complex 2 (TSC2) regulates cell migration and polarity through activation of CDC42 and RAC1. J Biol Chem 285:24987–24998PubMedCrossRef

47.

Lee A, Maldonado M, Baybis M, Walsh CA, Scheithauer B, Yeung R, Parent J, Weiner HL, Crino PB (2003) Markers of cellular proliferation are expressed in cortical tubers. Ann Neurol 53(5):668–673PubMedCrossRef

48.

Lee-Jones L, Aligianis I, Davies PA, Puga A, Farndon PA, Stemmer-Rachamimov A, Ramesh V, Sampson JR (2004) Sacrococcygeal chordomas in patients with tuberous sclerosis complex show somatic loss of TSC1 or TSC2. Genes Chromosomes Cancer 41:80–85PubMedCrossRef

49.

Lopes MB, Altermatt HJ, Scheithauer BW, Shepherd CW, VandenBerg SR (1996) Immunohistochemical characterization of subependymal giant cell astrocytomas. Acta Neuropathol 91:368–375PubMedCrossRef

50.

Ma J, Meng Y, Kwiatkowski DJ et al (2010) Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade. J Clin Investig 120:103–114PubMedCrossRef

51.

Maldonado M, Baybis M, Newman D, Kolson DL, Chen W, McKhann G 2nd, Gutmann DH, Crino PB (2003) Expression of ICAM-1, TNF-alpha, NFkappaB, and MAP kinase in tubers of the tuberous sclerosis complex. Neurobiol Dis 14:279–290PubMedCrossRef

52.

Marcotte L, Aronica E, Baybis M, Crino PB (2012) Cytoarchitectural alterations are widespread in cerebral cortex in tuberous sclerosis complex. Acta Neuropathol 123:685–693PubMedCrossRef

53.

McMaster ML, Goldstein AM, Parry DM (2011) Clinical features distinguish childhood chordoma associated with tuberous sclerosis complex (TSC) from chordoma in the general paediatric population. J Med Genet 48:444–449PubMedCrossRef

54.

Meikle L, Talos DM, Onda H et al (2007) A mouse model of tuberous sclerosis: neuronal loss of Tsc1 causes dysplastic and ectopic neurons, reduced myelination, seizure activity, and limited survival. J Neurosci 27:5546–5558PubMedCrossRef

55.

Miyata H, Chiang AC, Vinters HV (2004) Insulin signaling pathways in cortical dysplasia and TSC-tubers: tissue microarray analysis. Ann Neurol 56(4):510–519PubMedCrossRef

56.

Mizuguchi M, Takashima S (2001) Neuropathology of tuberous sclerosis. Brain Dev 23(7):508–515PubMedCrossRef

57.

Napolioni V, Moavero R, Curatolo P (2009) Recent advances in neurobiology of tuberous sclerosis complex. Brain Dev 31:104–113PubMedCrossRef

58.

Nie D, Di Nardo A, Han JM et al (2010) Tsc2-Rheb signaling regulates EphA-mediated axon guidance. Nat Neurosci 13:163–172PubMedCrossRef

59.

Niida Y, Stemmer-Rachamimov AO, Logrip M, Tapon D, Perez R, Kwiatkowski DJ, Sims K, MacCollin M, Louis DN, Ramesh V (2001) Survey of somatic mutations in tuberous sclerosis complex (TSC) hamartomas suggests different genetic mechanisms for pathogenesis of TSC lesions. Am J Hum Genet 69:493–503PubMedCrossRef

60.

Oh WJ, Jacinto E (2011) mTOR complex 2 signaling and functions. Cell Cycle 10:2305–2316PubMedCrossRef

61.

Onda H, Crino PB, Zhang H, Murphey RD, Rastelli L, Gould Rothberg BE, Kwiatkowski DJ (2002) Tsc2 null murine neuroepithelial cells are a model for human tuber giant cells, and show activation of an mTOR pathway. Mol Cell Neurosci 21(4):561–574PubMedCrossRef

62.

Orlova KA, Tsai V, Baybis M et al (2010) Early progenitor cell marker expression distinguishes type II from type I focal cortical dysplasias. J Neuropath Exp Neurol 69(8):850–863PubMedCrossRef

63.

Osborne JP, Fryer A, Webb D (1991) Epidemiology of tuberous sclerosis. Ann NY Acad Sci 615:125–127PubMedCrossRef

64.

Park SH, Pepkowitz SH, Kerfoot C et al (1997) Tuberous sclerosis in a 20-week gestation fetus: immunohistochemical study. Acta Neuropathol 94:180–186PubMedCrossRef

65.

Parker WE, Orlova KA, Heuer GG et al (2011) Enhanced epidermal growth factor, hepatocyte growth factor, and vascular endothelial growth factor expression in tuberous sclerosis complex. Am J Pathol 178:296–305PubMedCrossRef

66.

Peterson TR, Laplante M, Thoreen CC et al (2009) DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 137:873–886PubMedCrossRef

67.

Potter CJ, Huang H, Xu T (2001) Drosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size. Cell 105:357–368PubMedCrossRef

68.

Prabowo AS, Anink JJ, Lammens M et al (2013) Fetal Brain Lesions in Tuberous Sclerosis Complex: TORC1 Activation and Inflammation. Brain Pathol 23:45–49

69.

Qin W, Chan JA, Vinters HV et al (2010) Analysis of TSC cortical tubers by deep sequencing of TSC1, TSC2 and KRAS demonstrates that small second-hit mutations in these genes are rare events. Brain Pathol 20:1096–1105PubMedCrossRef

70.

Qin W, Kozlowski P, Taillon BE et al (2010) Ultra deep sequencing detects a low rate of mosaic mutations in tuberous sclerosis complex. Hum Genet 127:573–582PubMedCrossRef

71.

Reith RM, Way S, McKenna J 3rd, Haines K, Gambello MJ (2011) Loss of the tuberous sclerosis complex protein tuberin causes Purkinje cell degeneration. Neurobiol Dis 43:113–122PubMedCrossRef

72.

Ridler K, Bullmore ET, De Vries PJ et al (2001) Widespread anatomical abnormalities of grey and white matter structure in tuberous sclerosis. Psychol Med 31:1437–1446PubMedCrossRef

73.

Roach ES, Smith M, Huttenlocher P et al (1992) Diagnostic criteria: tuberous sclerosis complex. Report of the Diagnostic Criteria Committee of the National Tuberous Sclerosis Association. J Child Neurol 7:221–224PubMedCrossRef

74.

Roach ES, Gomez MR, Northrup H (1998) Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J Child Neurol 3:624–628CrossRef

75.

Rosner M, Hengstschlager M (2004) Tuberin binds p27 and negatively regulates its interaction with the SCF component Skp2. J Biol Chem 279:48707–48715PubMedCrossRef

76.

Rüegg S, Baybis M, Juul H, Dichter M, Crino PB (2007) Effects of rapamycin on gene expression, morphology, and electrophysiological properties of rat hippocampal neurons. Epilepsy Res 77:85–92PubMedCrossRef

77.

Sancak O, Nellist M, Goedbloed M et al (2005) Mutational analysis of the TSC1 and TSC2 genes in a diagnostic setting: genotype–phenotype correlations and comparison of diagnostic DNA techniques in tuberous sclerosis complex. Eur J Hum Genet 13:731–741PubMedCrossRef

78.

Sarbassov DD, Ali SM, Sabatini DM (2005) Growing roles for the mTOR pathway. Curr Opin Cell Biol 17:596–603PubMedCrossRef

79.

Sato N, Koinuma J, Ito T et al (2010) Activation of an oncogenic TBC1D7 (TBC1 domain family, member 7) protein in pulmonary carcinogenesis. Genes Chromosomes Cancer 49:353–367PubMed

80.

Sharma M, Ralte A, Arora R, Santosh V, Shankar SK, Sarkar C (2004) Subependymal giant cell astrocytoma: a clinicopathological study of 23 cases with special emphasis on proliferative markers and expression of p53 and retinoblastoma gene proteins. Pathology 36:139–144PubMedCrossRef

81.

Sosunov AA, Wu X, Weiner HL, Mikell CB, Goodman RR, Crino PB, McKhann GM 2nd (2008) Tuberous sclerosis: a primary pathology of astrocytes? Epilepsia 49(Suppl 2):53–62PubMedCrossRef

82.

Takahashi DK, Dinday MT, Barbaro NM, Baraban SC (2004) Abnormal cortical cells and astrocytomas in the Eker rat model of tuberous sclerosis complex. Epilepsia 45:1525–1530PubMedCrossRef

83.

Takei H, Adesina AM, Powell SZ (2009) Solitary subependymal giant cell astrocytoma incidentally found at autopsy in an elderly woman without tuberous sclerosis complex. Neuropathology 29:181–186PubMedCrossRef

84.

Talos DM, Kwiatkowski DJ, Cordero K, Black PM, Jensen FE (2008) Cell-specific alterations of glutamate receptor expression in tuberous sclerosis complex cortical tubers. Ann Neurol 63:454–465PubMedCrossRef

85.

Tavazoie SF, Alvarez VA, Ridenour DA et al (2005) Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. Nat Neurosci 8:1727–1734PubMedCrossRef

86.

Tee AR, Manning BD, Roux PP et al (2003) Tuberous sclerosis complex gene products, tuberin and hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr Biol 13:1259–1268PubMedCrossRef

87.

Tsai V, Parker WE, Orlova KA et al (2012) Fetal Brain mTOR Signaling Activation in Tuberous Sclerosis Complex. Cereb Cortex. October 18 [Epub Ahead of print]

88.

Tsai PT, Hull C, Chu Y et al (2012) Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature 488:647–651. doi:10.1038/nature11310

89.

Tyburczy ME, Kotulska K, Pokarowski P, Mieczkowski J, Kucharska J, Grajkowska W, Roszkowski M, Jozwiak S, Kaminska B (2010) Novel proteins regulated by mTOR in subependymal giant cell astrocytomas of patients with tuberous sclerosis complex and new therapeutic implications. Am J Pathol 176(4):1878–1890PubMedCrossRef

90.

Uhlmann EJ, Wong M, Baldwin RL et al (2002) Astrocyte-specific TSC1 conditional knockout mice exhibit abnormal neuronal organization and seizures. Ann Neurol 52:285–296PubMedCrossRef

91.

van Slegtenhorst M, de Hoogt R, Hermans C et al (1997) Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 277:805–808PubMedCrossRef

92.

van Slegtenhorst M, Verhoef S, Tempelaars A et al (1999) Mutational spectrum of the TSC1 gene in a cohort of 225 tuberous sclerosis complex patients: no evidence for genotype-phenotype correlation. J Med Genet 36:285–289PubMed

93.

Vaughn J, Hagiwara M, Katz J, Roth J, Devinsky O, Weiner H, Milla S (2012) MRI Characterization and longitudinal study of focal cerebellar lesions in a young tuberous sclerosis cohort. AJNR Am J Neuroradiol. 2012 Sep 6 [Epub ahead of print]

94.

Way SW, McKenna J 3rd, Mietzsch U et al (2009) Loss of Tsc2 in radial glia models the brain pathology of tuberous sclerosis complex in the mouse. Hum Mol Genet 18:1252–1265PubMedCrossRef

95.

White R, Hua Y, Lynch DR, Scheitauer B, Crino PB (2001) Differential transcription of neurotransmitter receptor subunits and uptake sites in giant cells and dysplastic neurons in cortical tubers. Ann Neurol 49:67–78PubMedCrossRef

96.

Wong M, Ess K, Uhlmann EJ et al (2003) Impaired astrocyte glutamate transport in a mouse epilepsy model of tuberous sclerosis complex. Ann Neurol 54:251–256PubMedCrossRef

97.

Wong M, Crino PB (2012) Tuberous sclerosis and epilepsy: role of astrocytes. Glia 60:1244–1250PubMedCrossRef

98.

Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124:471–484PubMedCrossRef

99.

Xu L, Zeng LH, Wong M (2009) Impaired astrocyte gap junction coupling and potassium buffering in a mouse model of tuberous sclerosis complex. Neurobiol Dis 34:291–299PubMedCrossRef

100.

Yang Q, Inoki K, Kim E, Guan KL (2006) TSC1/TSC2 and Rheb have different effects on TORC1 and TORC2 activity. Proc Natl Acad Sci USA 103:6811–6816PubMedCrossRef

101.

Yu Y, Yoon SO, Poulogiannis G et al (2011) Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science 332:1322–1326PubMedCrossRef

102.

Yuan E, Tsai PT, Greene-Colozzi E, Sahin M, Kwiatkowski DJ, Malinowska IA (2012) Graded loss of tuberin in an allelic series of brain models of TSC correlates with survival, and biochemical, histological and behavioral features. Hum Mol Genet 21:4286–4300PubMedCrossRef

103.

Zeng Z, dos Sarbassov D, Samudio IJ et al (2007) Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood 109:3509–3512PubMedCrossRef

104.

Zeng LH, Xu L, Gutmann DH, Wong M (2008) Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann Neurol 63:444–453PubMedCrossRef

105.

Zeng LH, Rensing NR, Zhang B et al (2011) Tsc2 gene inactivation causes a more severe epilepsy phenotype than Tsc1 inactivation in a mouse model of tuberous sclerosis complex. Hum Mol Genet 20:445–454PubMedCrossRef

106.

Zeng LH, Bero AW, Zhang B, Holtzman DM, Wong M (2010) Modulation of astrocyte glutamate transporters decreases seizures in a mouse model of tuberous sclerosis complex. Neurobiol Dis 37(3):764–771PubMedCrossRef

107.

Zhou J, Shrikhande G, Xu J et al (2011) Tsc1 mutant neural stem/progenitor cells exhibit migration deficits and give rise to subependymal lesions in the lateral ventricle. Genes Dev 25:1595–1600PubMedCrossRef

Title: Evolving neurobiology of tuberous sclerosis complex
Author: Peter B. Crino
Publication date: 01-03-2013
Publisher: Springer-Verlag
Published in: Acta Neuropathologica / Issue 3/2013
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-013-1085-x

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Evolving neurobiology of tuberous sclerosis complex

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2013

VMA21 deficiency prevents vacuolar ATPase assembly and causes autophagic vacuolar myopathy

OTX2 sustains a bivalent-like state of OTX2-bound promoters in medulloblastoma by maintaining their H3K27me3 levels

DNA methylation profiling of medulloblastoma allows robust subclassification and improved outcome prediction using formalin-fixed biopsies

Nervous system involvement in von Hippel–Lindau disease: pathology and mechanisms

Secretory meningiomas are defined by combined KLF4 K409Q and TRAF7 mutations

Inclusions in frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP) and amyotrophic lateral sclerosis (ALS), but not FTLD with FUS proteinopathy (FTLD-FUS), have properties of amyloid