Antoni Matilla Dueñas Director Unidad Básica, Traslacional y Neurogenética Molecular en Neurociencias y Coordinador Red Iberoamericana RIBERMOV

Transcripción

1 Antoni Matilla Dueñas Director Unidad Básica, Traslacional y Neurogenética Molecular en Neurociencias y Coordinador Red Iberoamericana RIBERMOV Editor Genética Revista The Cerebellum Instituto de Investigación Germans Trias y Pujol (IGTP) Universitat Autònoma de Barcelona Badalona (Barcelona)

2 Environmental Risk Factors Genetic Risk Factors Epigenome + Proteome Complex Neurological diseases

3 Genetic Analysis in Neurology: The Next 10 Years. Genetic Analysis in Neurology: The Next 10 Years. Pittman, Alan; Hardy, John JAMA Neurology. 70(6): , June DOI: /jamaneurol

4 Genetic Analysis in Neurology: The Next 10 Years. Genetic Analysis in Neurology: The Next 10 Years. Pittman, Alan; Hardy, John JAMA Neurology. 70(6): , June DOI: /jamaneurol

5 Genetic Analysis in Neurology: The Next 10 Years. Genetic Analysis in Neurology: The Next 10 Years. Pittman, Alan; Hardy, John JAMA Neurology. 70(6): , June DOI: /jamaneurol

6 Variant classification according to their consequence or position on transcripts. The set of consequence terms, defined by the Sequence Ontology (

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8 The Neurogenomics View of Neurological Diseases. Tsuji, Shoji; MD, PhD JAMA Neurology. 70(6): , June DOI: /jamaneurol

9 The Neurogenomics View of Neurological Diseases. Tsuji, Shoji; MD, PhD JAMA Neurology. 70(6): , June DOI: /jamaneurol

10 Genes & Disease OMIM, 27 Septiembre 2013

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12 Las ataxias espinocerebelosas Las ataxias espinocerebelosas son genéticamente heterogéneas

13 Las ataxias espinocerebelosas Las ataxias espinocerebelosas son genéticamente heterogéneas SCA29 SCA15 SCA37 SCA25 SCA19/SCA22 SCA7 EA6 ADNOA SCA1 SCA21 EA5 SCA34 ADSA SCA20 SCA5 EA3 SCA30 SCA12 SCA17 SCA18 SCA X DRPLA EA1 SPAX1 ADHD SCA11 SCA28 SCA26 SCA6 EA2 SCA35 SCA23 SCA36 SCA8 SCA2 SCA27 SCA3 SCA31 SCA4 EA7 SCA13 SCA14 SCA Y A Matilla-Dueñas. The ever expanding spinocerebellar ataxias. Editorial. Cerebellum 11 (4), (2012)

14 V:1 VI:1 IV: IV:2 IV: IV: III:1 IV: IV:6 4 6 III:2 IV: II:1 III:3 II:2 IV: V:2 V:3 V:4 V:5 V:6 V:7 V:8 38 VI:2 VI: IV: I:1 IV:10 III:4 6 6 IV: IV:12 III: V:9 V:10 V: VI:4 I:2 VI:5 IV: IV:14 II:3 II:4 III:6 III:7 III:8 III:9 III:10 IV: V: IV: IV: IV: V: II:5 V: III:11 IV:19 II: III:12 VI: IV:20 V: V: VI:7 6 4 IV: V: IV: V: IV:23 I II III??? Markers D1S319 D1S2661 D1S417 D1S2652 D1S475 D1S200 D1S2742 D1S2690 D1S2867 rs IV V VI

15 Figure 2. A and B, Sagittal and coronal T1-weighted magnetic resonance imaging scans of the brain of patient IV:5. The eye movements during vertical fixed saccades (C) (20[degrees] amplitude; top line, upward saccades; bottom line, downward saccades [arrows]) and smooth pursuit (D) (0.4 Hz; 16[degrees] amplitude; and peak velocity, 40[degrees]/s) are shown for patient IV:6. The asterisks indicate saccadic intrusions. New Subtype of Spinocerebellar Ataxia With Altered Vertical Eye Movements Mapping to Chromosome 1p32. Serrano-Munuera, Carmen; Corral-Juan, Marc; Stevanin, Giovanni; San Nicolas, Hector; Roig, Carles; MD, PhD; Corral, Jordi; Campos, Berta; de Jorge, Laura; Morcillo- Suarez, Carlos; Navarro, Arcadi; Forlani, Sylvie; MD, PhD; Durr, Alexandra; MD, PhD; Kulisevsky, Jaime; MD, PhD; Brice, Alexis; MD, PhD; Sanchez, Ivelisse; Volpini, Victor; MD, PhD; Matilla-Duenas, Antoni JAMA Neurology. 70(6): , June DOI: /jamaneurol

16 Ataxias Sindrómicas y No Sindrómicas Ataxias no sindrómicas Secuenciación masiva panel de 30 genes: ADCK3, AFG3L2, ANO10, APTX, BEAN, CACNA1A, CACNB4, FGF14, FXN, IFRD1, ITPR1, KCNA1, KCNC3, MTP, MTPAP, PDYN, PIK3R5, PLEKHG4, PRKCG, SACS, SETX, SLC1A3, SPTBN2, SYNE1, SYT14, TDP1, TGM6, TTBK2, TTPA, ZNF592 Ataxias Sindrómicas Secuenciación masiva panel de 55 genes: ABCB7, ABHD12, ADCK3, ALS2, ANG, ATCAY, ATM, ATR, CA8, CEP290, C10orf2, COQ2, COQ9, CYP27A1, DNAJC19, EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5, FIG4, FLVCR1, FMR1, FUS, GJC2, GPR56, HSPD1, ITM2B, KCNJ10, KIAA0226, MRE11A, NPHP1, OPA1, PAX6, PC, PDHA1, PDSS1, PDSS2, PEX7, PHYH, PLP, POLG, POLR3A, PRNP, PRPS1, RPGRIP1L, SCN8A, SETX, SIL1, SLC9A6, SOD1, TARDBP, TMEM67, VAPB, VLDLR

17 Enfermedad de Parkinson Parkinson, Enfermedad, tipos 1, 4, 5, 8, 11, 13, 17, 18, autosómica dominante Parkinson, enfermedad, tipos 2, 6, 7, 9, 14, 15, autosómica recesiva, de inicio temprano Secuenciación masiva panel de 7 genes: EIF4G1, GIGYF2, HTRA2, LRRK2, SNCA, UCHL1, VPS35 Secuenciación masiva panel de 6 genes: ATP13A2, FBXO7, PARK2, PARK7, PINK1, PLA2G6 Parkinson asociado a demencia frontotemporal, Enfermedad de Pick y parálisis supranuclear progresivay Demencia con cuerpos de Lewy Secuenciación masiva panel de 2 genes: MAPT, SNCB Parkinson, Enfermedad sindrómica y no sindrómica Secuenciación masiva panel de 23 genes: ADH1C, ATP13A2, ATP1A3, DCTN1, EIF4G1, FBXO7, GBA, GCH1, GIGYF2, HTRA2, LRRK2, MAPT, PARK2, PARK7, PDXK, PINK1, PLA2G6, POLG1, SNCA, SNCAIP, SNCB, UCHL1, VPS35

18 SCA1* SCA2 SCA3 HD AO/expanded 60.6% (p<0.0001) 64% (p= ) 60.5% (p<0.0001) 63.4% (p<2x10-16 ) AO/expanded + normal 66.4% (p<0.003) 65% (p=0.1300) % (p<2x10-16 )* AO/expanded + normal + gender 78.5% (p<0.0001) % (p<0.0001) - AO: Edad de inicio *Matilla-Dueñas,..., Volpini. Hum Mol Gen 1993.

19 Scatterplot of SCA2 CAG repeat length and age of onset in Cuban SCA2 patients; red and yellow lines denote one standard deviation boundaries for age of onset. Pulst S et al. Brain 2005;128:

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24 Understanding Neurological Disease Mechanisms in the Era of Epigenetics. Qureshi, Irfan; Mehler, Mark JAMA Neurology. 70(6): , June DOI: /jamaneurol

25 JAMA Neurology. 70(6): , June DOI: /jamaneurol

26 Farmacogenética Fármacos a la carta

27 Molecular pathways triggering neurodegeneration in the spinocerebellar ataxias A.Matilla-Dueñas, M.Corral-Juan & I.Sánchez. Cerebellum 9 (2), (2010)

28 Tipos de muerte celular [programada]: MCP APOPTOSIS (MCP tipo I): Intrínseca (Mitocondria/apoptosoma) y Extrínseca AUTOFAGIA (MCP tipo II): incluye mitofagia MUERTE CELULAR CITOPLÁSMICA (MCP tipo III): NECROSIS PROGRAMADA NECROPTOSIS* PARAPTOSIS PARTHANATOS: mediada por poly ADP-ribose polimerasa-1 (PARP1) y AIF DEGENERACIÓN NEURONAL OSCURA (DARK CELL DEGENERATION) ANOIKIS ENTOSIS PIROPTOSIS: respuesta antimicrobiana durante inflamación (caspasa-1)

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30 PCs in aging SCA2 transgenic mice die by dark cell degeneration) ( 10 months old SCA2-58Q) Cerebellum September; 11(3): doi: /s

31 Rutas Celulares y Moleculares en Neurodegeneración 2. Agregación proteica: plegado, insolubilidad 3. Degradación: proteasoma, autofagia apoptosis, necroptosis, DCD, etc. 5. Excitotoxicidad: Glutamato 7. Homeostasis Calcio 10. Transporte axonal

32 Las ataxias están causadas por alteraciones de rutas moleculares y proteínas comunes - 54 interacciones proteicas relacionadas con ataxias hereditarias: recesivas (AF) y dominantes. Factores modificadores Muchas regulatorias (directa o indirectamente) de transcripción.

33 Figure 1. Strategy for constructing tissue-specific networks and predicting phenotype-associated genes. Guan Y, Gorenshteyn D, Burmeister M, Wong AK, et al. (2012) Tissue-Specific Functional Networks for Prioritizing Phenotype and Disease Genes. PLoS Comput Biol 8(9): e doi: /journal.pcbi

34 Figure 6. Top connected genes to Atcay in the cerebellum-specific network reveals likely ataxia candidates. Guan Y, Gorenshteyn D, Burmeister M, Wong AK, et al. (2012) Tissue-Specific Functional Networks for Prioritizing Phenotype and Disease Genes. PLoS Comput Biol 8(9): e doi: /journal.pcbi

35 OD 650 nm 0,25 0,20 0,15 0,10 0,05 0,00 y = 0,0002x R² = 0, pmoles Phosphate

36 Pp2a holoenzyme composition and signalling are altered in SCA1. Sánchez I et al. Hum. Mol. Genet. 2013;22:

37 The proposed model of the ataxin-1 induced alterations of Pp2a activity and holoenzyme composition in the cerebellum of 5-week-old mice. Sánchez I et al. Hum. Mol. Genet. 2013;22:

38 Neuronal morphological alterations in ATXN1[30Q] and ATXN1[80Q] expressing differentiated SH-SY5Y cells and the effects of ANP32A co-expression on neurite morphology. Sánchez I et al. Hum. Mol. Genet. 2013;22:

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40 Identification of ATXN1 toxicity and aggregation modifiers using cell-based assays. Petrakis et al. 2011

41 Sacsin knockdown reduces the incidence of cells with large nuclear inclusions of polyglutamine-expanded ataxin-1. Hum Mol Genet May 1; 18(9):

42 Cribados in vivo para identificar y/o validar moduladores fenotipo atáxico

43 Selective Positive Modulator of Calcium-Activated Potassium Channels Exerts Beneficial Effects in a Mouse Model of Spinocerebellar Ataxia Type 2. Chemistry & Biology Volume 19, Issue

44 Large-Scale Screen for Modifiers of Ataxin-3-Derived Polyglutamine-Induced Toxicity in Drosophila PLoS ONE 7(11): 2012

45 PLoS ONE 7(11): 2012

46 Modifiers of spinocerebellar ataxia 3-associated neurodegeneration in Drosophila Hum Mol Genet Jan 1;21(1): Epub 2011 Sep 23.

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49 IFNγ induces frataxin accumulation in FRDA cells. Tomassini B et al. Hum. Mol. Genet. 2012;21:

50 In vivo IFNγ treatment upregulates human frataxin in DRG of FRDA mice. Tomassini B et al. Hum. Mol. Genet. 2012;21:

51 In vivo IFNγ treatment improves locomotor and motor coordination performances and prevents neurodegeneraton in FRDA mice. Tomassini B et al. Hum. Mol. Genet. 2012;21:

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53 Injertos de Precursores neuronales en el cerebelo atáxico Chintawar, S. et al. J. Neurosci. 2009;29:

54 Pandolfo, M. et al. Grafting neural precursor cells promotes functional recovery in an SCA1 mouse model. The Journal of Neuroscience. 29, (2009).

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56 Unidad de Investigación Básica, Traslacional y de Neurogenética Molecular en Neurociencias dirigida por el Dr. Matilla. Dra. Ivelisse Sánchez Díaz Eudald Balagué Cabasés Maria Queralt Caus Capdevila Patricia Piñol Jurado Marc Corral-Juan Alba Bellot Sáez Ariadna Navarro Aragall Mireia Seró Torres Ainània Tècul Torres

57 Colaboraciones y Financiación Departamento Neurociencias y Servicio Neurología: Dr. Antoni Dávalos Dr. Ramiro Álvarez Dr. Jaume Coll Dr. Domingo Escudero Dra. Lourdes Ispierto Dra. Pilar Latorre Dr. Javier Arpa Dr. Manuel Posada Dra. Carmen Serrano NEURODEGNET: RARE-BESTpractices: en preparación REDAPED: en preparación RIBERMOV: Dr. Victor Volpini Berta Campos Laura de Jorge Jordi Corral Héctor SanNicolás Dr. Alexis Brice Dra. Alexandra Durr Dr. Giovanni Stevanin Dr. Arcadi Navarro Dr. Carles Morcillo Dr. Massimo Pandolfo Dr. Xavier Gomis-Rüth Dr. Iñaki de Diego

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