Almaguer-Mederos LE, Almaguer-Gotay D, Cuello-Almarales D, Aguilera-Rodríguez R

Idioma: Español
Referencias bibliográficas: 50
Paginas: 76-90
Archivo PDF: 775.46 Kb.

RESUMEN

Introducción: Las enfermedades poliglutamínicas constituyen un grupo de afecciones neurodegenerativas aún incurables, causadas por la expansión de repeticiones CAG. En los últimos años se ha demostrado que la autofagia forma parte del proceso fisiopatológico asociado a enfermedades poliglutamínicas.
Objetivos: Revisar los hallazgos más recientes en torno a la asociación de la autofagia al proceso fisiopatológico en enfermedades poliglutamínicas, destacando el alcance de estos descubrimientos para la concepción y desarrollo de estrategias terapéuticas para el tratamiento de pacientes afectados.
Métodos: Se realizó una búsqueda de investigaciones publicadas en las bases de datos PubMed, HINARI, EBSCO y Highwire Press, a través del uso de palabras clave relevantes al tema.
Resultados: Se incluye una actualización de los estudios publicados que han analizado distintos aspectos de la autofagia en el contexto de enfermedades poliglutamínicas. Se abordan los mecanismos implicados y la utilidad de la estimulación de la autofagia como estrategia terapéutica potencial.
Conclusiones: La diversidad de vías a través de las cuales la autofagia puede ser estimulada, incrementa las probabilidades de éxito de la modulación de la autofagia como estrategia terapéutica para enfermedades poliglutamínicas; no obstante, la eficacia y seguridad de los candidatos terapéuticos identificados para el tratamiento de enfermedades poliglutamínicas deben ser evaluadas con mayor profundidad.

REFERENCIAS (EN ESTE ARTÍCULO)

1. Orr HT. Polyglutamine neurodegeneration: Expanded glutamines enhance native functions. Curr Opin Genet Dev 2012; 22: 251-255.

2. Blum ES, Schwendeman AR, Shaham S. PolyQ disease: misfiring of a developmental cell death program? Trends Cell Biol 2013; 23: 168-174.

3. Klionsky DJ, Codogno P, Cuervo AM, Deretic V, Elazar Z, Fueyo-Margareto J, et al. A comprehensive glossary of autophagy-related molecules and processes. Autophagy 2010; 6: 438-448.

4. Komatsu M, Ueno T, Waguri S, Uchiyama Y, Kominami E, Tanaka K. Constitutive autophagy: vital role in clearance of unfavorable proteins in neurons. Cell Death and Differentiation 2007; 14: 887-894.

5. Wirawan E, Vanden Berghe T, Lippens S, Agostinis P, Vandenabeele P. Autophagy: for better or for worse. Cell Res 2012; 22:43-61.

6. Togashi K, Wakatsuki S, Furuno A, Tokunaga S, Nagai Y, Araki T. Na+/H+ exchangers induce autophagy in neurons and inhibit polyglutamine-induced aggregate formation. PLoS ONE 2013; 8: e81313.

7. Codogno P, Meijer AJ. Autophagy and signaling: their role in cell survival and cell death. Cell Death and Differentiation 2005; 12: 1509-1518.

8. Min HJ, Ko EA, Wu J, Kim ES, Kwon MK, Kwak MS, et al. Chaperone-like activity of high-mobility group box 1 protein and its role in reducing the formation of polyglutamine aggregates. J Immunol 2013; 190: 1797-1806.

9. Holmberg CI, Staniszewski KE, Mensah KN, Matouschek A, Morimoto RI. Inefficient degradation of truncated polyglutamine proteins by the proteasome. EMBO J 2004; 23: 4307-4318.

10. Bachmann RA, Kim JH, Wu AL, Park IH, Chen J. A nuclear transport signal in mammalian target of rapamycin is critical for its cytoplasmic signaling to S6 kinase 1. J Biol Chem 2006; 281: 7357-7363.

11. Atwal RS, Xia J, Pinchev D, Taylor J, Epand RM, Truant R. Huntingtin has a membrane association signal that can modulate huntingtin aggregation, nuclear entry and toxicity. Hum Mol Genet 2007; 16: 2600-2615.

12. Atwal RS, Truant R. A stress sensitive ER membrane-association domain in Huntingtin protein defines a potential role for Huntingtin in the regulation of autophagy. Autophagy 2008; 4: 91-93.

13. Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, Ueno T, Koike M, Uchiyama Y, Komkinami E, Tanaka K. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 2006; 441: 819-820.

14. Steffan JS. Does Huntingtin play a role in selective macroautophagy? Cell Cycle 2010; 9: 3401- 3413.

15. Shibata M, Lu T, Furuya T, Degterev A, Mizushima N, Yoshimori T, et al. Regulation of Intracellular Accumulation of Mutant Huntingtin by Beclin 1. JBC 2006; 281: 14474–14485.

16. Heng MY, Duong DK, Albin RL, Tallaksen-Greene SJ, Hunter JM, Lesort MJ, et al. Early autophagic response in a novel knock-in model of Huntington disease. Human Molecular Genetics 2010; 19: 3702–3720.

17. Martinez-Vicente M, Talloczy Z, Wong E, Tang G, Koga H, Kaushik S, et al. Cargo recognition failure is responsible for inefficient autophagy in Huntington’s disease. Nature Neuroscience 2010; 13: 567-76.

18. Carra S, Sivilotti M, Chávez Zobel AT, Lambert H, Landry J. HspB8, a small heat shock protein mutated in human neuromuscular disorders, has in vivo chaperone activity in cultured cells. Hum Mol Genet 2005; 14: 1659-69.

19. Zheng S, Clabough EBD, Sarkar S, Futter M, Rubinsztein DC, Zeitlin SO. Deletion of the Huntingtin polyglutamine stretch enhances neuronal autophagy and longevity in mice. PLoS Genet 2010; 6: e1000838.

20. Metzger S, Saukko M, Van Che H, Tong L, Puder Y, Riess O, Nguyen HP. Age at onset in Huntington’s disease is modified by the autophagy pathway: implication of the V471A polymorphism in Atg7. Hum Genet 2010; 128: 453-459.

21. Chen S-F, Kang M-L, Chen Y-Ch, Tang H-W, Huang Ch-W, Li W-H, et al. Autophagy-related gene 7 is downstream of heat shock protein 27 in the regulation of eye morphology, polyglutamine toxicity, and lifespan in Drosophila. J Biomed Sci 2012; 19: 52.

22. Martin DDO, Heit RJ, Yap MC, Davidson MW, Hayden MR, Berthiaume LG. Identification of a post-translationally myristoylated autophagy-inducing domain released by caspase cleavage of Huntingtin. Hum Molec Genet 2014; 23: 3166-3179.

23. 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.

24. McMahon SJ, Pray-Grant MG, Schieltz D, Yates JR 3rd, Grant PA. Polyglutamine-expanded spinocerebellar ataxia-7 protein disrupts normal SAGA and SLIK histone acetyltransferase activity. Proc Natl Acad Sci U S A 2005; 102: 8478-8482.

25. Mookerjee S, Papanikolaou T, Guyenet SJ, Sampath V, Lin A, Vitelli C, et al. Post-translational modification of ataxin-7 at lysine-257 prevents autophagy-mediated turnover of an N-terminal caspase-7 cleavage fragment. J Neurosci 2009; 29: 15134-15144.

26. Yu X, Ajayi A, Boga NR, Ström A-L. Differential degradation of full-length and cleaved Ataxin-7 fragments in a novel stable inducible SCA7 model. J Mol Neurosci 2012; 47: 219-233.

27. Rusmini P, Bolzoni E, Crippa V, Onesto E, Sau D, Galbiati M, Piccolella M, Poletti A. Proteasomal and autophagic degradative activities in spinal and bulbar muscular atrophy. Neurobiology of Disease 2010; 40: 361-369.

28. Montie HL, Cho MS, Holder L, Liu Y, Tsvetkov AS, Finkbeiner S, et al. Cytoplasmic retention of polyglutamine-expanded androgen receptor ameliorates disease via autophagy in a mouse model of spinal and bulbar muscular atrophy. Hum Mol Genet 2009; 18: 1937-50.

29. Pandey UB, Nie Z, Batlevi Y, McCray BA, Ritson GP, Nedelsky NB, et al. HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature 2007; 447: 859-63.

30. Rusmini P, Crippa V, Giorgetti E, Boncoraglio A, Cristofani R, Carra S, Poletti A. Clearance of the mutant androgen receptor in motoneuronal models of spinal and bulbar muscular atrophy. Neurobiol Aging 2013; 34: 2585-2603.

31. Suzuki Y, Yazawa I. Pathological accumulation of atrophin-1 in dentatorubralpallidoluysian atrophy. Int J Clin Exp Pathol. 2011; 4: 378-384.

32. Nisoli I, Chauvin JP, Napoletano F, Calamita P, Zanin V, Fanto M, Charroux B. Neurodegeneration by polyglutamine Atrophin is not rescued by induction of autophagy. Cell Death and Differentiation 2010; 1-11.

33. Napoletano F, Occhi S, Calamita P, Volpi V, Blanc E, Charroux B, et al. Polyglutamine Atrophin provoques neurodegeneration in Drosophila by repressing fat. EMBO J 2011; 30: 945-958.

34. Rubinsztein DC, Gestwicki JE, Murphy LO, Klionsky DJ. Potential therapeutic applications of autophagy. Nature Reviews 2007; 6: 304-312.

35. Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 2004; 36: 585-595.

36. Menzies FM, Huebener J, Renna M, Bonin M, Riess O, Rubinsztein DC. Autophagy induction reduces mutant ataxin-3 levels and toxicity in a mouse model of spinocerebellar ataxia type 3. Brain 2010; 133: 93-104.

37. Wyttenbach A, Hands S, King MA, Lipkow K, Tolkovsky AM. Amelioration of protein misfolding disease by rapamycin Translation or autophagy? Autophagy 2008; 4: 542-545.

38. Ravikumar B y Rubinsztein DC. Role of autophagy in the clearance of mutant huntingtin: A step towards therapy? Molecular Aspects of Medicine 2006; 27: 520-527.

39. Sarkar S, Krishna G, Imarisio S, Saiki S, O’Kane CJ, Rubinsztein DC. A rational mechanism for combination treatment of Huntington’s disease using lithium and rapamycin. Hum Mol Genet 2008; 17: 170-178.

40. Williams A, Sarkar S, Cuddon P, Ttofi EK, Saiki S, Siddiqi FH, et al. Novel targets for Huntington’s disease in an mTOR-independent autophagy pathway. Nature Chemical Biology 2008; 4: 295-305.

41. Renna M, Jimenez-Sanchez M, Sarkar S, Rubinsztein DC. Chemical inducers of autophagy that enhance the clearance of mutant proteins in neurodegenerative diseases. JBC 2010; 285: 11061- 11067.

42. Zhang L, Yu J, Pan H, Hu P, Hao Y, Cai W et al. Small molecule regulators of autophagy identified by an image-based high-throughput screen. Proc Natl Acad Sci USA 2007; 104: 19023-19028.

43. Sarkar S, Davies JE, Huang Z, Tunnacliffe A, Rubinsztein DC. Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein. J Biol Chem 2007; 282: 5641-5652.

44. Rose C, Menzies FM, Renna M, Acevedo-Arozena A, Corrochano S, Sadiq O, et al. Rilmenidine attenuates toxicity of polyglutamine expansions in a mouse model of Huntington’s disease. Human Molecular Genetics 2010; 19: 2144-2153.

45. Harron DW. Distinctive features of rilmenidine possibly related to its selectivity for imidazoline receptors. Am. J. Hypertens 1992; 5: 91S-98S.

46. Reid JL. Update on rilmenidine: clinical benefits. Am. J. Hypertens 2001; 14: 322S-324S.

47. WHO. International clinical trial registry platform: Huntington’s Disease Rilmenidine Safety Trial. URL: http://apps.who.int/trialsearch/ Trial2.aspx?TrialID= EUCTR2009-018119-14-GB. [22.01.2015].

48. Bauer PO, Goswami A, Wong HK, Okuno M, Kurosawa M, Yamada M, et al. Harnessing chaperonemediated autophagy for the selective degradation of mutant huntingtin protein. Nature Biotechnology 2010; 28: 256-263.

49. Shoji-Kawata S, Sumpter R, Leveno M, Campbell GR, Zou Z, Kinch L. Identification of a candidate therapeutic autophagy–inducing peptide. Nature 2013; 494: 201-206.

50. Shin BH, Lim Y, Oh HJ, Park SM, Lee S-K, et al. Pharmacological activation of Sirt1 ameliorates polyglutamine-induced toxicity through the regulation of autophagy. PLoS ONE 2013; 8: e64953.