Magaña JJ, Velázquez-Pérez L, Cortés H, Hernández-Hernández O, Cisneros B

Idioma: Español
Referencias bibliográficas: 56
Paginas: 123-131
Archivo PDF: 513.08 Kb.

RESUMEN

La ataxia espinocerebelosa tipo 2 (SCA2) es una enfermedad neurodegenerativa con un patrón de herencia autosómico dominante, caracterizada por un cuadro clínico multisistémico que afecta principalmente al sistema nervioso somático y autónomo. La SCA2 es causada por un aumento en el número de repetidos del trinucleótido CAG, localizados en la región codificadora 5’ del gen ATXN2, lo que origina la incorporación de un segmento de poliglutaminas en el dominio N-terminal de la proteína mutante. Un mayor número de repetidos CAG se ha asociado con un inicio más temprano y manifestaciones más severas de la enfermedad en generaciones subsecuentes de una familia afectada. En este trabajo se presenta una recapitulación de las evidencias experimentales que han permitido definir los mecanismos moleculares asociados con la SCA2. Además se describe, de manera detallada, la participación de la ataxina-2 en diferentes procesos celulares, como la maduración del ARN mensajero, la regulación de la traducción, la endocitosis y la señalización mediada por calcio. Finalmente, tomando en consideración las bases moleculares de la SCA2 se discuten las posibles estrategias de terapia génica para revertir o aminorar la enfermedad.

REFERENCIAS (EN ESTE ARTÍCULO)

1. Velázquez-Pérez L, Rodríguez-Labrada R, García-Rodríguez JC, Almaguer-Mederos LE, Cruz-Mariño T, Laffita-Mesa JM. A Comprehensive review of spinocerebellar ataxia type 2 in Cuba. Cerebellum. 2011; 10 (2): 184-198.

2. Magaña JJ, Velázquez-Pérez L, Cisneros B. Spinocerebellar ataxia type 2: clinical presentation, molecular mechanisms, and therapeutic perspectives. Mol Neurobiol. 2013; 47: 90-104.

3. Auburger GW. Spinocerebellar ataxia type 2. Handb Clin Neurol. 2012; 103: 423-436.

4. Saleem Q, Choudhry S, Mukerji M, Bashyam L, Padma MV, Chakravarthy A et al. Molecular analysis of autosomal dominant hereditary ataxias in the Indian population: high frequency of SCA2 and evidence for a common founder mutation. Hum Genet. 2000; 106: 179-187.

5. Velázquez-Pérez L, García R, Santos FN, Paneque HM, Medina HE, Hechavarría PR. Epidemiology of Cuban hereditary ataxias. Rev Neurol. 2001; 32: 606-611.

6. Alonso E, Martínez-Ruano L, DeBiase I, Mader C, Ochoa A, Yescas P et al. Distinct distribution of autosomal dominant spinocerebellar ataxia in the Mexican population. Mov Disord. 2007; 22: 1050-1053.

7. Magaña JJ, Tapia-Guerrero YS, Velázquez-Pérez L, Cerecedo-Zapata CM, Maldonado-Rodríguez M, Jano-Ito J et al. Analysis of CAG repeats in five SCA loci in Mexican population: epidemiological evidence of a SCA7 founder effect. Clin Genet. 2014; 85: 159-165.

8. Magaña JJ, Vergara MD, Sierra-Martínez M, García-Jiménez E, Rodríguez-Antonio F, Gómez M del R et al. Molecular analysis of the CAG repeat among patients with type-2 spinocerebellar ataxia in the Mexican population. Gac Med Mex. 2008; 144: 413-418.

9. Sahba S, Nechiporuk A, Figueroa KP, Nechiporuk T, Pulst SM. Genomic structure of the human gene for spinocerebellar ataxia 2 (SCA2) on chromosome 12q24.1. Genomics. 1998; 47: 359-364.

10. Sanpei K, Takano H, Igarashi S, Sato T, Oyake M, Sasaki H et al. Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT. Nat Genet. 1996; 14: 277-284.

11. Mao R, Aylsworth AS, Potter N, Wilson WG, Breningstall G, Wick MJ et al. Childhood-onset ataxia: testing for large CAG-repeats in SCA2 and SCA7. Am J Med Genet. 2002; 110: 338-345.

12. Giunti P, Sabbadini G, Sweeney MG, Davis MB, Veneziano L, Mantuano E et al. The role of SCA2 trinucleotide repeat expansion in 89 autosomal dominant cerebellar ataxia families: frequency, clinical and genetics correlates. Brain. 1998; 121: 459-467.

13. Orr HT, Zoghbi HY. Trinucleotide repeat disorders. Annu Rev Neurosci. 2007; 30: 575-621.

14. Ellegren H. Heterogeneous mutation processes in human microsatellite DNA sequences. Nat Genet. 2000; 24: 400-402.

15. Bauer PO, Nukina N. The pathogenic mechanisms of polyglutamine diseases and current therapeutic strategies. J Neurochem. 2009; 110: 1737-1765.

16. Magaña JJ, Cisneros B. Perspectives on gene therapy in myotonic dystrophy type 1. J Neurosci Res. 2011; 89: 275-285.

17. Van de Loo S, Eich F, Nonis D, Auburger G, Nowock J. Ataxin-2 associates with rough endoplasmic reticulum. Exp Neurol. 2009; 215: 110-118.

18. Turnbull VJ, Storey E, Tarlac V, Walsh R, Stefani D, Clark R et al. Different ataxin-2 antibodies display different immunoreactive profiles. Brain Res. 2004; 1027 (1-2): 103-116.

19. Huynh DP, Del Bigio MR, Ho DH, Pulst SM. Expression of ataxin-2 in brains from normal individuals and patients with Alzheimer’s disease and spinocerebellar ataxia 2. Ann Neurol. 1999; 45 (2): 232-241.

20. Rubinsztein DC, Wyttenbach A, Rankin J. Intracellular inclusions, pathological markers in diseases caused by expanded polyglutamine tracts? J Med Genet. 1999; 36 (4): 265-270.

21. Taroni F, DiDonato S. Pathways to motor incoordination: the inherited ataxias. Nat Rev Neurosci. 2004; 5 (8): 641-655.

22. Koyano S, Iwabuchi K, Yagishita S, Kuroiwa Y, Uchihara T. Paradoxical absence of nuclear inclusion in cerebellar Purkinje cells of hereditary ataxias linke to CAG expansion. J Neurol Neurosurg Psychiatry. 2002; 73 (4): 450-452.

23. Kretzschmar D, Tschäpe J, Bettencourt Da Cruz A, Asan E, Poeck B, Strauss R et al. Glial and neuronal expression of polyglutamine proteins induce behavioral changes and aggregate formation in drosophila. Glia. 2005; 49 (1): 59-72.

24. Boy J, Schmidt T, Schumann U, Grasshoff U, Unser S, Holzmann C. A transgenic mouse model of spinocerebellar ataxia type 3 resembling late disease onset and gender-specific instability of CAG repeats. Neurobiol Dis. 2010; 37 (2): 284-293.

25. Albrecht M, Golatta M, Wullner U, Lengauer T. Structural and functional analysis of ataxin-2 and ataxin-3. Eur J Biochem. 2004; 271: 3155-3170.

26. Satterfield TF, Pallanck LJ. Ataxin-2 and its drosophila homolog, ATX2, physically assemble with polyribosomes. Hum Mol Genet. 2006; 15: 2523-2532.

27. Tharun S. Roles of eukaryotic Lsm proteins in the regulation of mRNA function. Int Rev Cell Mol Biol. 2009; 272: 149-189.

28. Ralser M, Albrecht M, Nonhoff U, Lengauer T, Lehrach H, Krobitsch S. An integrative approach to gain insights into the cellular function of human ataxin-2. J Mol Biol. 2005; 346: 203-214.

29. Bravo J, Aguilar-Henonin L, Olmedo G, Guzmán P. Four distinct classes of proteins as interaction partners of the PABC domain of Arabidopsis thaliana Poly(A)-binding proteins. Mol Genet Genomics. 2005; 272: 651-665.

30. Shibata H, Huynh DP, Pulst SM. A novel protein with RNA-binding motifs interacts with ataxin-2. Hum Mol Genet. 2000; 9: 1303-1313.

31. Lee JA, Tang ZZ, Black DL. An inducible change in Fox-1/A2BP1 splicing modulates the alternative splicing of downstream neuronal target exons. Genes Dev. 2009; 23: 2284-2293.

32. Tsien JZ, Huerta PT, Tonegawa S. The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell. 1996; 87: 1327-1338.

33. Lim J, Hao T, Shaw C, Patel AJ, Szabo G, Rual JF et al. A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. Cell. 2006; 125: 801-814.

34. Kozlov G, Safaee N, Rosenauer A, Gehring K. Structural basis of binding of P-body-associated proteins GW182 and ataxin-2 by the Mlle domain of poly(A)-binding protein. J Biol Chem. 2010; 285: 13599-13606.

35. Ciosk R, DePalma M, Priess JR. ATX-2, the C. elegans ortholog of ataxin 2, functions in translational regulation in the germline. Development. 2004; 131: 4831-4841.

36. Vernet C, Artzt K. STAR, a gene family involved in signal transduction and activation of RNA. Trends Genet. 1997; 13: 479-484.

37. Swisher KD, Parker R. Localization to, and effects of Pbp1, Pbp4, Lsm12, Dhh1, and Pab1 on stress granules in saccharomyces cerevisiae. PLoS One. 2010; 5: e10006.

38. Huynh DP, Scoles DR, Nguyen D, Pulst SM. The autosomal recessive juvenile Parkinson disease gene product, parkin, interacts with and ubiquitinates synaptotagmin XI. Hum Mol Genet. 2003; 12: 2587-2597.

39. Imai Y, Soda M, Inoue H, Hattori N, Mizuno Y, Takahashi R. An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell. 2001; 105: 891-902.

40. Ralser M, Nonhoff U, Albrecht M, Lengauer T, Wanker EE, Lehrach H et al. Ataxin-2 and huntingtin interact with endophilin-A complexes to function in plastin-associated pathways. Hum Mol Genet. 2005; 14: 2893-2909.

41. Soubeyran P, Kowanetz K, Szymkiewicz I, Langdon WY, Dikic I. Cbl-CIN85-endophilin complex mediates ligand induced downregulation of EGF receptors. Nature. 2002; 416: 183-187.

42. Satterfield TF, Jackson SM, Pallanck LJ. A drosophila homolog of the polyglutamine disease gene SCA2 is a dosage-sensitive regulator of actin filament formation. Genetics. 2002; 162: 1687-1702.

43. Huynh DP, Figueroa K, Hoang N, Pulst SM. Nuclear localization or inclusion body formation of ataxin-2 are not necessary for SCA2 pathogenesis in mouse or human. Nat Genet. 2000; 26: 44-50.

44. Aguiar J, Fernández J, Aguilar A, Mendoza Y, Vazquez M, Suárez J et al. Ubiquitous expression of human SCA2 gene under the regulation of the SCA2 self promoter cause specific Purkinje cell degeneration in transgenic mice. Neurosci Lett. 2006; 392: 202-206.

45. Liu J, Tang TS, Tu H, Nelson O, Herndon E, Huynh DP et al. Deranged calcium signaling and neurodegeneration in spinocerebellar ataxia type 2. J Neurosci. 2009; 29: 9148-9162.

46. Pirker W, Back C, Gerschlager W, Laccone F, Alesch F. Chronic thalamic stimulation in a patient with spinocerebellar ataxia type 2. Mov Disord. 2003; 18: 222-225.

47. Freund HJ, Barnikol UB, Nolte D, Treuer H, Auburger G, Tass PA et al. Subthalamic-thalamic DBS in a case with spinocerebellar ataxia type 2 and severe tremor-A unusual clinical benefit. Mov Disord. 2007; 22: 732-735.

48. Ristori G, Romano S, Visconti A, Cannoni S, Spadaro M, Frontali M et al. Riluzole in cerebellar ataxia: A randomized, double-blind, placebo-controlled pilot trial (CME) (LOE Classification). Neurology. 2010; 74: 839-845.

49. Bonini NM, La Spada AR. Silencing polyglutamine degeneration with RNAi. Neuron. 2005; 48: 715-718.

50. Matilla-Dueñas A, Sánchez I, Corral-Juan M, Dávalos A, Alvarez R, Latorre P. Cellular and molecular pathways triggering neurodegeneration in the spinocerebellar ataxias. Cerebellum. 2010; 9: 148-166.

51. Wong HK, Bauer PO, Kurosawa M et al. Blocking acid-sensing ion channel 1 alleviates Huntington’s disease patology via an ubiquitin-proteosome system-dependent mechanism. Hum Mol Genet. 2008; 17: 3223-3235.

52. Pollitt SK, Pallos J, Shao J, Desai UA, Ma AA, Thompson LM et al. A rapid cellular FRET assay of polyglutamine aggregation identifies a novel inhibitor. Neuron. 2003; 40: 685-694.

53. Wood NI, Pallier PN, Wanderer J, Morton AJ. Systemic administration of Congo red does not improve motor or cognitive function in R6/2 mice. Neurobiol Dis. 2007; 25: 342-353.

54. Karpuj MV, Becher MW, Springer JE, Chabas D, Youssef S, Pedotti R et al. Prolonged survival and decreased abnormal movements in transgenic model of Huntington disease, with administration of the transglutaminase inhibitor cystamine. Nat Med. 2002; 8: 143-149.

55. Ferrante RJ, Andreassen OA, Dedeoglu A, Ferrante KL, Jenkins BG, Hersch SM et al. Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington’s disease. J Neurosci. 2002; 22: 1592-1599.

56. Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S et al. Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med. 2000; 6: 797-801.