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Genetics and Epigenetics in Parkinson´S Disease Genetics and epigenetics in Parkinson´s disease. Luis Navarro Sánchez. Thesis supervisor: Jordi Pérez Tur. Unitat de Genètica Molecular, Institut de Biomedicina de València, CSIC. Doctoral studies: Biotechnology. Facultat de Ciències Biològiques, Universitat de València. Tras preguntas y más preguntas y miedo y nervios y ansiedad y más ansiedad y bloqueos y periodos depresivos y tristeza y mucha, pero mucha, mierda… acabas. Tarde y reventado, pero acabas. Y lo único que quieres es pasar página y que esto no te pase más nunca. ¿Y? Pues que te surgen más preguntas y más miedo y más nervios…. Y te das cuenta de que vives en un puto bucle científico que se está comiendo tu vida. ¿Y? No lo sé, estoy en ello. Terapia y medicación, supongo. Aunque la autodestrucción y los realities son muy apetecibles. En primer lugar, las formalidades. Gracias Jordi por dejarme que trabajara en la UGM. A estas alturas, creo que los dos nos habremos planteado muchas veces si fue una buena decisión, pero ya da igual. A continuación, el momento pasteleo, aunque si no sé dar un abrazo, no penséis que esto me va a salir fluido. Y menos aún, estando sobrio. Y que no se me enfade nadie si no he puesto su nombre o si no he escrito un parrafazo lacrimógeno y azucarado exaltando la belleza de nuestra relación. Si dejo que leas esto, significa que también eres importante para mí. Lo mejor de todo este tiempo sois, de calle, vosotros y vosotras: Bea, Carolina, Eva, Fer, LauraA, LauraG, María, Marta, Pili, Silvia, Vicente/Andreu y VicenteH. Mis amig@s, con l@s que he vivido, he sentido y he crecido…. y me he desafasao, sí, que seguro que estáis pensando en el dragón y/o en otros momentazos. Lo mejor de la UGM era su gente. Ali, Isa, Lou, Elena, Manoli, Sole, Nuria, l@s narrativ@s... y muchas más. Personas maravillosas que forman parte de mi vida, lo cual no es fácil. Y para acabar los agradecimientos: Les doy las gracias a mis padres y a mi hermana, porque son los tres pilares fundamentales de mi vida. Son mi refugio (literalmente en estos últimos meses). Esta tesis me la dedico a mí. Sí, a mí. Por lo malo, por los errores, por crecer, por saber perder, por aguantar, por terminar y por intentar aprender durante este largo camino tanto a nivel personal como profesional todo lo que he podido. Hasta aquí llega la parte suculenta, donde enseño y escondo, como siempre. Ahora llega la ciencia, a la que, aunque tenga mis dudas, creo que tengo algo que aportar, y de la que quiero vivir trabajando con dignidad. P.D. Negaré tener cualquier relación con este texto; tengo una fachada que mantener. Este trabajo pude llevarlo a cabo gracias a la beca JAEPre del CSIC que disfruté del 2008 al 2011. De no ser por ella, todo este proceso, ya difícil de por sí, lo hubiera sido muchísimo más. ABBREVIATIONS. ᴥ 5mC: 5-methylcytosine. ᴥ 6-OHDA: 6-hydroxidopamine. ᴥ AD: Alzheimer´s disease. ᴥ ALS: amyotrophic lateral sclerosis. ᴥ Syn: -synuclein. ᴥ CBD: corticobasal degeneration. ᴥ CI: confidence interval. ᴥ C.I.: cognitive impairment. ᴥ CMA: chaperone-mediated autophagy. ᴥ df: degrees of freedom. ᴥ DLB: dementia with Lewy bodies. ᴥ ER: endoplasmic reticulum. ᴥ FTD: frontotemporal dementia. ᴥ FTLD: frontotemporal lobar degeneration. ᴥ GD: Gaucher disease. ᴥ GWAS: genome-wide association study. ᴥ Hcy: homocysteine. ᴥ HD: Huntington´s disease. ᴥ HWE: Hardy-Weinberg equilibrium. ᴥ LB: Lewy bodies. ᴥ LD: linkage disequilibrium. ᴥ L-dopa: levodopa. ᴥ M.C.I.: mild cognitive impairment. ᴥ MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. ᴥ N.C.: normal cognition. ᴥ NE: nuclear envelope. ᴥ OR: odds ratio. ᴥ PD: Parkinson´s disease. ᴥ PSP: progressive supranuclear palsy. ᴥ ROS: reactive oxygen species. ᴥ SN: substantia nigra. ᴥ SNpc: substantia nigra pars compacta. ᴥ SNpr: substantia nigra pars reticulata. ᴥ TSS: transcription start site. INDEX. I. INTRODUCTION. ..................................................................................................... 1 I.1. Definition of PD. ....................................................................................... 1 I.2. Anatomical perspective. ........................................................................ 2 I.3. Clinical perspective.................................................................................. 9 I.4. Diagnosis. ................................................................................................ 12 I.5. Treatment. .. ............................................................................................ 16 I.5.a. Pharmacological therapy. ........................................................... 16 I.5.b. Non-pharmacological therapy. .................................................. 21 I.6. Incidence and prevalence. .................................................................. 25 I.7. Etiology. .................................................................................................... 27 I.7.a. Environmental factors. ................................................................. 27 I.7.b. Genetic factors. .............................................................................. 30 I.8. Familial PD. .............................................................................................. 33 I.8.a. SNCA. ................................................................................................. 33 I.8.b. PRKN. ................................................................................................. 41 I.8.c. PINK1. ................................................................................................ 46 I.8.d. DJ-1. ................................................................................................... 51 I.8.e. LRRK2. ............................................................................................... 56 I.9. Other PARK loci. ..................................................................................... 65 I.9.a. PARK3. ............................................................................................... 65 I.9.b. UCHL1 (PARK5). ............................................................................... 66 I.9.c. ATP13A2 (PARK9)............................................................................ 68 I.9.d. PARK10. ............................................................................................ 70 I.9.e. GIGYF2 (PARK11) and PARK12. ................................................... 71 I.9.f. HtrA2 (PARK13). ............................................................................... 73 I.9.g. PLA2G6 (PARK14). .......................................................................... 75 I.9.h. FBXO7 (PARK15). ........................................................................... 77 I.9.i. PARK16. ............................................................................................. 80 I.9.j. PARK17 and PARK18. ...................................................................... 82 I.10. Genetic susceptibility factors. ......................................................... 86 I.10.a. MAPT. .............................................................................................. 86 I.10.b. GBA. ................................................................................................. 90 I.10.c. NR4A2. ............................................................................................ 95 I.11. Dementia. .............................................................................................. 98 I.11.a. Alzheimer´s disease. ................................................................ 101 I.11.b. Frontotemporal dementia. .................................................... 108 I.11.c. Huntington´s disease. ............................................................... 114 I.11.d. Creutzfeldt-Jakob disease. ..................................................... 117 I.12. Others. ................................................................................................. 122 I.12.a. NFE2L2 and KEAP1. .................................................................. 122 I.12.b. LAMP-2A and hsc70. ................................................................ 123 I.12.c. Neurotrophic factors (CDNF, MANF, BDNF). ...................... 126 I.12.d. ARMCX family. ........................................................................... 131 I.12.e. TOR1A. ........................................................................................ 133 I.12.f. GSK3 .......................................................................................... 138 I.12.g. Homocysteine. ........................................................................... 140 I.12.h. TOMM40. ..................................................................................... 146 I.13. Epigenetics in PD. .............................................................................. 150 II. OBJECTIVES. ....................................................................................................... 169 III. MATERIAL AND METHODS............................................................................ 173 Subjects. ....................................................................................................... 173 Cognitive evaluation. ................................................................................ 182 III.1. Genetics in PD. .................................................................................... 183 DNA extraction. ..................................................................................... 183
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