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)
Environmental
Risk
Factors
Genetic
Risk
Factors
Epigenome
+
Proteome
Complex Neurological
diseases
Genetic Analysis in Neurology: The Next 10 Years.
Genetic Analysis in Neurology: The Next 10 Years. Pittman, Alan; Hardy, John JAMA Neurology. 70(6):696-702, June 2013. DOI: 10.1001/jamaneurol.2013.2068
Genetic Analysis in Neurology: The Next 10 Years. Pittman, Alan; Hardy, John JAMA Neurology. 70(6):696-702, June 2013. DOI: 10.1001/jamaneurol.2013.2068
Genetic Analysis in Neurology: The Next 10 Years.
Genetic Analysis in Neurology: The Next 10 Years.
Genetic Analysis in Neurology: The Next 10 Years. Pittman, Alan; Hardy, John JAMA Neurology. 70(6):696-702, June 2013. DOI: 10.1001/jamaneurol.2013.2068
Variant classification according to their consequence or position on
transcripts. The set of consequence terms, defined by the Sequence
Ontology (http://www.sequenceontology.org/)
The Neurogenomics View of Neurological Diseases. Tsuji, Shoji; MD, PhD JAMA Neurology. 70(6):689-694, June 2013. DOI: 10.1001/jamaneurol.2013.734
The Neurogenomics View of Neurological Diseases. Tsuji, Shoji; MD, PhD JAMA Neurology. 70(6):689-694, June 2013. DOI: 10.1001/jamaneurol.2013.734
Genes & Disease
OMIM, 27 Septiembre 2013
Las ataxias espinocerebelosas
Las ataxias espinocerebelosas son genéticamente heterogéneas
EA7
SCA25
SCA29 SCA15
SCA30
SCA12
SCA1
SCA17
SCA21
SCA18
SCA20SCA5
1 2 3 4 5 6 7 8 9 10 11 X
12
DRPLA
SCA2
16
SCA31 SCA4
13
SCA8
SCA27SCA3
14
SCA11
15 17
SCA28
18
SCA26
SCA6EA2
SCA13SCA14
19
SCA23
20 21
SCA10
22 Y
SCA7
ADSA
ADHD
EA1
EA3
EA5
EA6 ADNOA
SPAX1
SCA32
SCA34
SCA35
SCA36
SCA19/SCA22
SCA37
Las ataxias espinocerebelosas
Las ataxias espinocerebelosas son genéticamente heterogéneas
A Matilla-Dueñas. The ever expanding spinocerebellar ataxias.
Editorial. Cerebellum 11 (4), 821-827 (2012)
I
II
III
IV
V
VI
MarkersD1S319D1S2661
D1S417D1S2652
D1S475D1S200D1S2742
D1S2690D1S2867
rs151062149
VI:1
V:1
II:1 II:2
?
III:1 III:3III:2 III:5III:4
IV:1
2 11 23 22 11 11 11 42 11 11 1
IV:2 IV:5
1 22 12 12 21 22 14 62 23 11 2
IV:6
1 22 12 11 21 21 14 61 21 11 2
IV:7
1 22 12 12 21 22 14 62 23 11 2
IV:8
2 42 12 11 21 23 49 21 11 11 1
V:6
1 42 12 12 21 22 44 22 13 11 1
V:7
2 21 21 22 12 11 36 92 11 12 1
IV:10
2 21 12 11 21 21 16 61 21 11 1
IV:9 IV:11
2 21 12 11 21 21 16 61 21 11 1
IV:12
1 42 22 21 21 11 34 41 21 11 1
IV:13
1 42 22 21 21 11 34 41 21 11 1
IV:14
V:3
IV:4
4 21 11 22 12 21 37 71 24 21 1
V:538
2 41 13 12 21 21 11 72 11 41 1
IV:3
2 11 23 22 11 11 11 42 11 11 1
V:2 V:4 V:8
3 22 12 21 21 21 17 62 21 11 1
V:10
3 22 12 11 21 21 12 61 21 11 1
VI:2 VI:3
?
I:1
?
I:2
II:4II:3
III:6 III:7 III:8 III:9 III:10
4 22 12 11 21 23 16 62 22 11 2
IV:15
1 31 12 21 11 15 34 63 21 21 1
IV:16
3 11 12 12 21 25 14 63 21 11 2
IV:18
3 11 12 22 11 15 34 63 21 21 1
IV:17
5 21 11 12 21 21 16 93 11 11 1
V:12
3 21 12 12 21 25 14 93 11 11 1
V:13
3 21 12 12 21 25 14 93 11 11 1
II:5 II:6
III:11 III:12
IV:21
2 22 12 12 22 24 19 62 24 11 2
IV:22
2 32 22 22 22 24 19 62 14 51 1
V:18
2 22 22 22 22 24 49 92 24 41 1
V:17
2 32 22 22 22 24 19 62 14 51 1
IV:19
2 22 11 12 21 24 14 62 21 11 2
V:15
2 41 41 12 22 11 26 52 11 52 1
V:14
2 42 41 12 21 14 24 52 11 51 1
V:16
1 11 22 12 21 32 24 92 21 21 1
VI:6
4 14 21 12 21 31 25 91 25 12 1
VI:7
2 11 11 22 22 11 26 42 21 11 1
V:9 V:11
VI:4 VI:5
IV:23IV:20
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):764-771, June 2013. DOI: 10.1001/jamaneurol.2013.2311
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.
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
Ataxias Sindrómicas y No Sindrómicas
Parkinson, Enfermedad, tipos 1, 4, 5, 8, 11, 13, 17, 18, autosómica dominante
Secuenciación masiva panel de 7 genes: EIF4G1, GIGYF2, HTRA2, LRRK2, SNCA, UCHL1, VPS35
Parkinson, enfermedad, tipos 2, 6, 7, 9, 14, 15, autosómica recesiva, de inicio temprano
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
Enfermedad de Parkinson
SCA1* SCA2 SCA3 HD
AO/expanded 60.6%
(p<0.0001) 64%
(p= 0.0002) 60.5%
(p<0.0001) 63.4%
(p<2x10-16)
AO/expanded+ normal
66.4% (p<0.003)
65% (p=0.1300)
- 63.8%
(p<2x10-16)*
AO/expanded+ normal + gender
78.5% (p<0.0001)
- 61.1%
(p<0.0001) -
*Matilla-Dueñas, ..., Volpini. Hum Mol Gen 1993. AO: Edad de inicio
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;128:2297-2303
Understanding Neurological Disease Mechanisms in the Era of Epigenetics. Qureshi, Irfan; Mehler, Mark JAMA Neurology. 70(6):703-710, June 2013. DOI: 10.1001/jamaneurol.2013.1443
JAMA Neurology. 70(6):703-710, June 2013. DOI: 10.1001/jamaneurol.2013.1443
Farmacogenética
Fármacos a la carta
A.Matilla-Dueñas, M.Corral-Juan & I.Sánchez.
Cerebellum 9 (2), 148-166 (2010)
Molecular pathways triggering
neurodegeneration in the
spinocerebellar ataxias
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)
Cerebellum. 2012 September; 11(3): 630–639.
doi: 10.1007/s12311-010-0182-9
PCs in aging SCA2 transgenic mice die by dark cell degeneration)
( 10 months old SCA2-58Q)
Rutas Celulares y Moleculares en Neurodegeneración
apoptosis, necroptosis, DCD, etc.
2. Agregación proteica: plegado, insolubilidad
3. Degradación: proteasoma, autofagia
5. Excitotoxicidad: Glutamato
7. Homeostasis Calcio
10. Transporte axonal
- 54 interacciones proteicas relacionadas con ataxias hereditarias:
recesivas (AF) y dominantes.
Factores modificadores
Muchas regulatorias (directa o indirectamente) de transcripción.
Las ataxias están causadas por alteraciones
de rutas moleculares y proteínas comunes
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): e1002694. doi:10.1371/journal.pcbi.1002694
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): e1002694. doi:10.1371/journal.pcbi.1002694
http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002694
y = 0,0002x R² = 0,984
0,00
0,05
0,10
0,15
0,20
0,25
0 400 800 1200
OD
65
0 n
m
pmoles Phosphate
Pp2a holoenzyme composition and signalling are altered in SCA1.
Sánchez I et al. Hum. Mol. Genet. 2013;22:3425-3437
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;22:3425-3437
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;22:3425-3437
Identification of ATXN1 toxicity and aggregation modifiers using cell-based assays. Petrakis et al. 2011
Sacsin knockdown reduces the incidence
of cells with large nuclear inclusions of
polyglutamine-expanded ataxin-1.
Hum Mol Genet. 2009 May 1; 18(9): 1556–1565.
Cribados in vivo para identificar y/o validar moduladores fenotipo atáxico
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 10 2012 1340 - 1353
Large-Scale Screen for Modifiers of Ataxin-3-Derived Polyglutamine-Induced Toxicity in Drosophila
PLoS ONE 7(11): 2012
PLoS ONE 7(11): 2012
Hum Mol Genet. 2012 Jan 1;21(1):76-84. Epub 2011 Sep 23.
Modifiers of spinocerebellar ataxia 3-associated neurodegeneration in Drosophila
IFNγ induces frataxin accumulation in FRDA cells.
Tomassini B et al. Hum. Mol. Genet. 2012;21:2855-2861
In vivo IFNγ treatment upregulates human frataxin in DRG of FRDA mice.
Tomassini B et al. Hum. Mol. Genet. 2012;21:2855-2861
In vivo IFNγ treatment improves locomotor and motor coordination performances and prevents neurodegeneraton in FRDA mice.
Tomassini B et al. Hum. Mol. Genet. 2012;21:2855-2861
Chintawar, S. et al. J. Neurosci. 2009;29:13126-13135
Injertos de Precursores neuronales en el
cerebelo atáxico
Pandolfo, M. et al. Grafting neural precursor cells promotes functional recovery in
an SCA1 mouse model. The Journal of Neuroscience. 29, 13126-13135 (2009).
www.btnunit.org
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
Unidad de Investigación Básica, Traslacional y de Neurogenética
Molecular en Neurociencias dirigida por el Dr. Matilla.
Dr. Arcadi Navarro Dr. Carles Morcillo
Dra. Carmen Serrano
Dr. Antoni Dávalos Dr. Ramiro Álvarez Dr. Jaume Coll Dr. Domingo Escudero Dra. Lourdes Ispierto Dra. Pilar Latorre
Dr. Victor Volpini Berta Campos Laura de Jorge Jordi Corral Héctor SanNicolás
Dr. Alexis Brice Dra. Alexandra Durr Dr. Giovanni Stevanin
Dr. Massimo Pandolfo
Dr. Xavier Gomis-Rüth Dr. Iñaki de Diego
Dr. Manuel Posada
NEURODEGNET: www.neurodeg.net RARE-BESTpractices: en preparación REDAPED: en preparación RIBERMOV: www.ribermov.org
Departamento Neurociencias y Servicio Neurología:
Colaboraciones y Financiación
Dr. Javier Arpa