A proteomic survey of microtubule-associated proteins in a R402H TUBA1A mutant mouse


Autoři: Ines Leca aff001;  Alexander Phillips aff001;  Iris Hofer aff001;  Lukas Landler aff001;  Lyubov Ushakova aff001;  Thomas David Cushion aff001;  Gerhard Dürnberger aff001;  Karel Stejskal aff001;  Karl Mechtler aff001;  David Anthony Keays aff001;  Alexander William Phillips aff001
Působiště autorů: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria aff001;  Institute of Zoology, University of Natural Resources and Life Sciences (BOKU), Vienna, Austria aff002;  Gregor Mendel Institute (GMI), Austrian Academy of Sciences, Vienna Biocenter (VBC), Vienna, Austria aff003;  Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Vienna, Austria aff004;  Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Australia aff005;  Division of Neurobiology, Department Biology II, Ludwig-Maximilians-University Munich, Planegg-Martinsried 82152, Germany aff006
Vyšlo v časopise: A proteomic survey of microtubule-associated proteins in a R402H TUBA1A mutant mouse. PLoS Genet 16(11): e32767. doi:10.1371/journal.pgen.1009104
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1009104

Souhrn

Microtubules play a critical role in multiple aspects of neurodevelopment, including the generation, migration and differentiation of neurons. A recurrent mutation (R402H) in the α-tubulin gene TUBA1A is known to cause lissencephaly with cerebellar and striatal phenotypes. Previous work has shown that this mutation does not perturb the chaperone-mediated folding of tubulin heterodimers, which are able to assemble and incorporate into the microtubule lattice. To explore the molecular mechanisms that cause the disease state we generated a new conditional mouse line that recapitulates the R402H variant. We show that heterozygous mutants present with laminar phenotypes in the cortex and hippocampus, as well as a reduction in striatal size and cerebellar abnormalities. We demonstrate that homozygous expression of the R402H allele causes neuronal death and exacerbates a cell intrinsic defect in cortical neuronal migration. Microtubule sedimentation assays coupled with quantitative mass spectrometry demonstrated that the binding and/or levels of multiple microtubule associated proteins (MAPs) are perturbed by the R402H mutation including VAPB, REEP1, EZRIN, PRNP and DYNC1l1/2. Consistent with these data we show that the R402H mutation impairs dynein-mediated transport which is associated with a decoupling of the nucleus to the microtubule organising center. Our data support a model whereby the R402H variant is able to fold and incorporate into microtubules, but acts as a gain of function by perturbing the binding of MAPs.

Klíčová slova:

Hippocampus – Homozygosity – Lysosomes – Microtubules – Motor proteins – Neurons – Tubulins – Neuron migration


Zdroje

1. Breuss M, Keays DA (2014) Microtubules and neurodevelopmental disease: the movers and the makers. Adv Exp Med Biol 800: 75–96. doi: 10.1007/978-94-007-7687-6_5 24243101

2. Romero DM, Bahi-Buisson N, Francis F (2018) Genetics and mechanisms leading to human cortical malformations. Semin Cell Dev Biol 76: 33–75. doi: 10.1016/j.semcdb.2017.09.031 28951247

3. Ayala R, Shu T, Tsai LH (2007) Trekking across the brain: the journey of neuronal migration. Cell 128: 29–43. doi: 10.1016/j.cell.2006.12.021 17218253

4. Bertipaglia C, Goncalves JC, Vallee RB (2018) Nuclear migration in mammalian brain development. Semin Cell Dev Biol 82: 57–66. doi: 10.1016/j.semcdb.2017.11.033 29208348

5. Tanaka T, Serneo FF, Higgins C, Gambello MJ, Wynshaw-Boris A, et al. (2004) Lis1 and doublecortin function with dynein to mediate coupling of the nucleus to the centrosome in neuronal migration. J Cell Biol 165: 709–721. doi: 10.1083/jcb.200309025 15173193

6. Francis F, Koulakoff A, Boucher D, Chafey P, Schaar B, et al. (1999) Doublecortin is a developmentally regulated, microtubule-associated protein expressed in migrating and differentiating neurons. Neuron 23: 247–256. doi: 10.1016/s0896-6273(00)80777-1 10399932

7. Poirier K, Lebrun N, Broix L, Tian G, Saillour Y, et al. (2013) Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly. Nat Genet 45: 639–647. doi: 10.1038/ng.2613 23603762

8. Gleeson JG, Allen KM, Fox JW, Lamperti ED, Berkovic S, et al. (1998) Doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein. Cell 92: 63–72. doi: 10.1016/s0092-8674(00)80899-5 9489700

9. Reiner O, Carrozzo R, Shen Y, Wehnert M, Faustinella F, et al. (1993) Isolation of a Miller-Dieker lissencephaly gene containing G protein beta-subunit-like repeats. Nature 364: 717–721.

10. Jaglin XH, Chelly J (2009) Tubulin-related cortical dysgeneses: microtubule dysfunction underlying neuronal migration defects. Trends Genet 25: 555–566. doi: 10.1016/j.tig.2009.10.003 19864038

11. Jaglin XH, Poirier K, Saillour Y, Buhler E, Tian G, et al. (2009) Mutations in the beta-tubulin gene TUBB2B result in asymmetrical polymicrogyria. Nat Genet 41: 746–752. doi: 10.1038/ng.380 19465910

12. Breuss M, Heng JI, Poirier K, Tian G, Jaglin XH, et al. (2012) Mutations in the beta-tubulin gene TUBB5 cause microcephaly with structural brain abnormalities. Cell Rep 2: 1554–1562. doi: 10.1016/j.celrep.2012.11.017 23246003

13. Tischfield MA, Baris HN, Wu C, Rudolph G, Van Maldergem L, et al. Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance. Cell 140: 74–87. doi: 10.1016/j.cell.2009.12.011 20074521

14. Cushion TD, Paciorkowski AR, Pilz DT, Mullins JG, Seltzer LE, et al. (2014) De novo mutations in the beta-tubulin gene TUBB2A cause simplified gyral patterning and infantile-onset epilepsy. Am J Hum Genet 94: 634–641. doi: 10.1016/j.ajhg.2014.03.009 24702957

15. Breuss M, Fritz T, Gstrein T, Chan K, Ushakova L, et al. (2016) Mutations in the murine homologue of TUBB5 cause microcephaly by perturbing cell cycle progression and inducing p53 associated apoptosis. Development. doi: 10.1242/dev.131516 26903504

16. Tian G, Jaglin XH, Keays DA, Francis F, Chelly J, et al. (2010) Disease-associated mutations in TUBA1A result in a spectrum of defects in the tubulin folding and heterodimer assembly pathway. Hum Mol Genet 19: 3599–3613. doi: 10.1093/hmg/ddq276 20603323

17. Latremoliere A, Cheng L, DeLisle M, Wu C, Chew S, et al. (2018) Neuronal-Specific TUBB3 Is Not Required for Normal Neuronal Function but Is Essential for Timely Axon Regeneration. Cell Rep 24: 1865–1879 e1869. doi: 10.1016/j.celrep.2018.07.029 30110642

18. Tischfield MA, Baris HN, Wu C, Rudolph G, Van Maldergem L, et al. (2010) Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance. Cell 140: 74–87. doi: 10.1016/j.cell.2009.12.011 20074521

19. Aiken J, Buscaglia G, Aiken AS, Moore JK, Bates EA (2019) Tubulin mutations in brain development disorders: Why haploinsufficiency does not explain TUBA1A tubulinopathies. Cytoskeleton (Hoboken).

20. Keays DA, Tian G, Poirier K, Huang GJ, Siebold C, et al. (2007) Mutations in alpha-tubulin cause abnormal neuronal migration in mice and lissencephaly in humans. Cell 128: 45–57. doi: 10.1016/j.cell.2006.12.017 17218254

21. Kumar RA, Pilz DT, Babatz TD, Cushion TD, Harvey K, et al. (2010) TUBA1A mutations cause wide spectrum lissencephaly (smooth brain) and suggest that multiple neuronal migration pathways converge on alpha tubulins. Hum Mol Genet 19: 2817–2827. doi: 10.1093/hmg/ddq182 20466733

22. Poirier K, Keays DA, Francis F, Saillour Y, Bahi N, et al. (2007) Large spectrum of lissencephaly and pachygyria phenotypes resulting from de novo missense mutations in tubulin alpha 1A (TUBA1A). Hum Mutat 28: 1055–1064. doi: 10.1002/humu.20572 17584854

23. Pham CL, Morrissette NS (2019) The tubulin mutation database: A resource for the cytoskeleton community. Cytoskeleton (Hoboken) 76: 186–191. doi: 10.1002/cm.21514 30667171

24. Lowe J, Li H, Downing KH, Nogales E (2001) Refined structure of alpha beta-tubulin at 3.5 A resolution. J Mol Biol 313: 1045–1057. doi: 10.1006/jmbi.2001.5077 11700061

25. Aiken J, Moore JK, Bates EA (2019) TUBA1A mutations identified in lissencephaly patients dominantly disrupt neuronal migration and impair dynein activity. Hum Mol Genet 28: 1227–1243. doi: 10.1093/hmg/ddy416 30517687

26. Gorski JA, Talley T, Qiu M, Puelles L, Rubenstein JL, et al. (2002) Cortical excitatory neurons and glia, but not GABAergic neurons, are produced in the Emx1-expressing lineage. J Neurosci 22: 6309–6314. doi: 20026564 12151506

27. Molyneaux BJ, Arlotta P, Menezes JR, Macklis JD (2007) Neuronal subtype specification in the cerebral cortex. Nat Rev Neurosci 8: 427–437. doi: 10.1038/nrn2151 17514196

28. Bahi-Buisson N, Poirier K, Boddaert N, Saillour Y, Castelnau L, et al. (2008) Refinement of cortical dysgeneses spectrum associated with TUBA1A mutations. J Med Genet 45: 647–653. doi: 10.1136/jmg.2008.058073 18728072

29. Oegema R, Cushion TD, Phelps IG, Chung SK, Dempsey JC, et al. (2015) Recognizable cerebellar dysplasia associated with mutations in multiple tubulin genes. Hum Mol Genet 24: 5313–5325. doi: 10.1093/hmg/ddv250 26130693

30. Dubois NC, Hofmann D, Kaloulis K, Bishop JM, Trumpp A (2006) Nestin-Cre transgenic mouse line Nes-Cre1 mediates highly efficient Cre/loxP mediated recombination in the nervous system, kidney, and somite-derived tissues. Genesis 44: 355–360. doi: 10.1002/dvg.20226 16847871

31. Braun A, Breuss M, Salzer MC, Flint J, Cowan NJ, et al. (2010) Tuba8 is expressed at low levels in the developing mouse and human brain. Am J Hum Genet 86: 819–822; author reply 822–813. doi: 10.1016/j.ajhg.2010.03.019 20466094

32. Ori-McKenney KM, Xu J, Gross SP, Vallee RB (2010) A cytoplasmic dynein tail mutation impairs motor processivity. Nat Cell Biol 12: 1228–1234. doi: 10.1038/ncb2127 21102439

33. Tsai JW, Bremner KH, Vallee RB (2007) Dual subcellular roles for LIS1 and dynein in radial neuronal migration in live brain tissue. Nat Neurosci 10: 970–979. doi: 10.1038/nn1934 17618279

34. Shu T, Ayala R, Nguyen MD, Xie Z, Gleeson JG, et al. (2004) Ndel1 operates in a common pathway with LIS1 and cytoplasmic dynein to regulate cortical neuronal positioning. Neuron 44: 263–277. doi: 10.1016/j.neuron.2004.09.030 15473966

35. Gartz Hanson M, Aiken J, Sietsema DV, Sept D, Bates EA, et al. (2016) Novel alpha-tubulin mutation disrupts neural development and tubulin proteostasis. Dev Biol 409: 406–419. doi: 10.1016/j.ydbio.2015.11.022 26658218

36. Furuse T, Yamada I, Kushida T, Masuya H, Miura I, et al. (2012) Behavioral and neuromorphological characterization of a novel Tuba1 mutant mouse. Behav Brain Res 227: 167–174.

37. Bittermann E, Abdelhamed Z, Liegel RP, Menke C, Timms A, et al. (2019) Differential requirements of tubulin genes in mammalian forebrain development. PLoS Genet 15: e1008243. doi: 10.1371/journal.pgen.1008243 31386652

38. Reck-Peterson SL, Redwine WB, Vale RD, Carter AP (2018) The cytoplasmic dynein transport machinery and its many cargoes. Nat Rev Mol Cell Biol 19: 382–398. doi: 10.1038/s41580-018-0004-3 29662141

39. Hiscox S, Jiang WG (1999) Ezrin regulates cell-cell and cell-matrix adhesion, a possible role with E-cadherin/beta-catenin. J Cell Sci 112 Pt 18: 3081–3090. 10462524

40. Souphron J, Bodakuntla S, Jijumon AS, Lakisic G, Gautreau AM, et al. (2019) Purification of tubulin with controlled post-translational modifications by polymerization-depolymerization cycles. Nat Protoc 14: 1634–1660. doi: 10.1038/s41596-019-0153-7 30996262

41. Morotz GM, De Vos KJ, Vagnoni A, Ackerley S, Shaw CE, et al. (2012) Amyotrophic lateral sclerosis-associated mutant VAPBP56S perturbs calcium homeostasis to disrupt axonal transport of mitochondria. Hum Mol Genet 21: 1979–1988. doi: 10.1093/hmg/dds011 22258555

42. Nishimura AL, Mitne-Neto M, Silva HC, Richieri-Costa A, Middleton S, et al. (2004) A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet 75: 822–831. doi: 10.1086/425287 15372378

43. Park SH, Zhu PP, Parker RL, Blackstone C (2010) Hereditary spastic paraplegia proteins REEP1, spastin, and atlastin-1 coordinate microtubule interactions with the tubular ER network. J Clin Invest 120: 1097–1110. doi: 10.1172/JCI40979 20200447

44. Zuchner S, Wang G, Tran-Viet KN, Nance MA, Gaskell PC, et al. (2006) Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31. Am J Hum Genet 79: 365–369. doi: 10.1086/505361 16826527

45. Takahashi K, Sasaki T, Mammoto A, Takaishi K, Kameyama T, et al. (1997) Direct interaction of the Rho GDP dissociation inhibitor with ezrin/radixin/moesin initiates the activation of the Rho small G protein. J Biol Chem 272: 23371–23375. doi: 10.1074/jbc.272.37.23371 9287351

46. Johnson MW, Miyata H, Vinters HV (2002) Ezrin and moesin expression within the developing human cerebrum and tuberous sclerosis-associated cortical tubers. Acta Neuropathol 104: 188–196. doi: 10.1007/s00401-002-0540-x 12111362

47. Zajkowski T, Nieznanska H, Nieznanski K (2015) Stabilization of microtubular cytoskeleton protects neurons from toxicity of N-terminal fragment of cytosolic prion protein. Biochim Biophys Acta 1853: 2228–2239. doi: 10.1016/j.bbamcr.2015.07.002 26149502

48. Li XL, Wang GR, Jing YY, Pan MM, Dong CF, et al. (2011) Cytosolic PrP induces apoptosis of cell by disrupting microtubule assembly. J Mol Neurosci 43: 316–325. doi: 10.1007/s12031-010-9443-9 20838930

49. Encalada SE, Szpankowski L, Xia CH, Goldstein LS (2011) Stable kinesin and dynein assemblies drive the axonal transport of mammalian prion protein vesicles. Cell 144: 551–565. doi: 10.1016/j.cell.2011.01.021 21335237

50. Laquerriere A, Maillard C, Cavallin M, Chapon F, Marguet F, et al. (2017) Neuropathological Hallmarks of Brain Malformations in Extreme Phenotypes Related to DYNC1H1 Mutations. J Neuropathol Exp Neurol 76: 195–205. doi: 10.1093/jnen/nlw124 28395088

51. Weedon MN, Hastings R, Caswell R, Xie W, Paszkiewicz K, et al. (2011) Exome sequencing identifies a DYNC1H1 mutation in a large pedigree with dominant axonal Charcot-Marie-Tooth disease. Am J Hum Genet 89: 308–312.

52. Harms MB, Ori-McKenney KM, Scoto M, Tuck EP, Bell S, et al. (2012) Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy. Neurology 78: 1714–1720. doi: 10.1212/WNL.0b013e3182556c05 22459677

53. Gstrein T, Edwards A, Pristoupilova A, Leca I, Breuss M, et al. (2018) Mutations in Vps15 perturb neuronal migration in mice and are associated with neurodevelopmental disease in humans. Nat Neurosci 21: 207–217. doi: 10.1038/s41593-017-0053-5 29311744

54. Wisniewski JR, Zougman A, Nagaraj N, Mann M (2009) Universal sample preparation method for proteome analysis. Nat Methods 6: 359–362. doi: 10.1038/nmeth.1322 19377485

55. Smyth GK (2004) Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 3: Article3.

56. Raudvere U, Kolberg L, Kuzmin I, Arak T, Adler P, et al. (2019) g:Profiler: a web server for functional enrichment analysis and conversions of gene lists (2019 update). Nucleic Acids Res 47: W191–W198.

57. Tripathy R, Leca I, van Dijk T, Weiss J, van Bon BW, et al. (2018) Mutations in MAST1 Cause Mega-Corpus-Callosum Syndrome with Cerebellar Hypoplasia and Cortical Malformations. Neuron 100: 1354–1368 e1355.

58. Zala D, Hinckelmann MV, Yu H, Lyra da Cunha MM, Liot G, et al. (2013) Vesicular glycolysis provides on-board energy for fast axonal transport. Cell 152: 479–491. doi: 10.1016/j.cell.2012.12.029 23374344


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