Biologia molecular de la malaltia de Huntington. IP: Verónica Inés Brito

Presentació

El nostre grup està interessat en estudiar un nou nivell de regulació de l'expressió gènica que està intervingut per modificacions postranscripcionals de l'ARN conegut com Epitranscriptómica. Aquestes marques químiques o modificacions de l'ARN, són dinàmiques, poden ser molt abundants en el cervell i estar implicades en diferents processos neuronals regulant la funció de l'ARN neuronal.

El nostre principal objectiu és explorar i caracteritzar el paper d'aquestes modificacions i els factors regulatius de la maquinària epitranscriptòmica en l'inici i progressió de malalties neurodegeneratives, particularment, de la patologia de la malaltia de Huntington (EH). Per això hem desenvolupat una estratègia interdisciplinària que combina tècniques de transcriptòmica, mètodes bioquímics, immunohistoquímica i estudis funcionals en ratolins models de la malaltia.

PARAULES CLAU: Malaltia de Huntington, modificacions de l'ARN, reparació de l'ADN, activitat neuronal, epigenètica, huntingtina, splicing alternatiu, edició de gens CRISPR, disfunció sinàptica


Verónica Inés Brito
Investigador principal (Lector Serra Hunter)
veronica.brito@ub.edu



Maria Bergé Gardeñes
Estudiant de màster en Bioquímica, Biologia Molecular i Biomedicina
mariaberge01@gmail.com

 


Carla Castells Esteve
Assistent de recerca
carla.castells@ub.edu

 

ANTICS MEMBRES:

 


Anika Pupak
Estudiant de doctorat
(2019-2022)


Irene Rodriguez Navarro
Investigadora pre-doctoral
(2022-2023)

  • Identificació dels canvis epitranscripòmics associats a la desregulació transcripcional, la disfunció sinàptica i els dèficits cognitius i motors de l'EH.
     
  • Anàlisi i estudi del paper de les modificacions epigenètiques de l'ARN en la generació de fragments tòxics de la huntingtina mutada.

  • Dissecting the role of m6A as epigenetic guardian of somatic instability in Huntington´s disease

Ministerio de Ciencia, Innovación y Universidades
Programa consolidación investigadora. CNS2023-144738.
IP: Veronica Brito
Subvenció: 175.000 €
2024-2026

  • A pilot study of a novel molecular assay to quantify DNA repair synthesis in the HTT exon 1 as readout of somatic instability in Huntington´s Disease

European Huntington´s Disease Network
EHDN Seed fund 1296
IP: Veronica Brito
Subvenció: 50.000 €
2024-2025

  • Deciphering the role of  m6A RNA methylation as a new layer of gene expression regulation in Huntington´s disease pathology (MetHD) 

PID2020-116474RB-I00
Ministerio de Ciencia, Innovación y Universidades
IP: Veronica Brito
Subvenció: 140.000 €
2021-2024

  • Exploring m6A modifications as critical modulators of mutant huntingtin alternative splicing

Hereditary Disease Foundation (HDF)
IP: Veronica Brito
Subvenció: 63.000 €
2021-2022

  • Study of mitochondrial outcomes as biomarkers of Huntington´s Disease progression and/or readouts of pharmacological interventions

Huntington´s Disease Society of America (HDSA) Human Biology Program
IP: Veronica Brito
Subvenció: 63.000 €
2017-2018

Per a més informació sobre les publicacions de l’IP del grup podeu visitar els següents l’enllaços:

ORCID: 0000-0002-4137-0708
Scopus Author ID: 6701599747
Researcher ID: M-2112-2015
Loop Profile: 776206

 

Rodríguez-Urgellés E, Casas-Torremocha D, Sancho-Balsells A, Ballasch I, García-García E, Miquel-Rio L, Manasanch A, Del Castillo I, Chen W, Pupak A, Brito V, Tornero D, Rodríguez MJ, Bortolozzi A, Sanchez-Vives MV, Giralt A, Alberch J. Thalamic Foxp2 regulates output connectivity and sensory-motor impairments in a model of Huntington's Disease. Cell Mol Life Sci. 2023 Nov 21;80(12):367. doi: 10.1007/ s00018-023- 05015-z. PMID: 37987826

Espina M, Di Franco N, Brañas-Navarro M, Navarro IR, Brito V, Lopez-Molina L, Costas-Insua C, Guzmán M, Ginés S (2023) The GRP78-PERK axis contributes to memory and synaptic impairments in Huntington's disease R6/1 mice. Neurobiol Dis. 2023 Aug:184:106225. doi: 10.1016/ j.nbd.2023.106225. Epub 2023 Jul 11. PMID: 37442396

Pupak A, Rodríguez Navarro I, Sathasivam K, Essmann E, Singh A, del Toro D, Ginés S, Bates GP, Vang Ørom U, Marti E, Brito V. m6A RNA modification of mHtt intron 1 regulates the generation of Htt1a in Huntington’s Disease. Preprint bioRxiv (2023) doi: https://doi.org/10.1101/2023.11.10.566530

Sancho-Balsells A, Borràs-Pernas S, Brito V, Alberch J, Girault JA, Giralt A. Cognitive and Emotional Symptoms Induced by Chronic Stress Are Regulated by EGR1 in a Subpopulation of Hippocampal Pyramidal Neurons. Int J Mol Sci. 2023 Feb 14;24(4): 3833. doi: 10.3390/ ijms24043833 doi: 10.3390/ijms24043833. PMID: 36835243

Garcia-Forn M, Castany-Pladevall C, Golbano A, Pérez-Pérez J, Brito V, Kulisevsky J, Pérez-Navarro E. Lamin B1 and nuclear morphology in peripheral cells as new potential biomarkers to follow treatment response in Huntington's disease. Clin Transl Med. 2023 Feb;13(2): e1154. doi: 10.1002/ ctm2.1154. PMID: 36781300

Rodríguez-Urgellés E, Rodríguez-Navarro I, Ballasch I, Del Toro D, Del Castillo I, Brito V, Alberch J, Giralt A.  Postnatal Foxp2 regulates early psychiatric-like phenotypes and associated molecular alterations in the R6/1 transgenic mouse model of Huntington's disease. Neurobiol Dis. 2022 Oct 15:173:105854. doi: 10.1016/ j.nbd.2022.105854. Epub 2022 Aug 24. PMID: 36029989

Pupak A., Singh A, Sancho A, Espina M, Giralt A, Marti, E Vang Orom, U, Gines S, Brito V. Altered m6A RNA methylation contributes to hippocampal memory deficits in Huntington´s disease mice.  Cell Mol Life Sci. 2022 Jul 11; 79(8):416. doi: 10.1007/ s00018-022-04444-6. PMID: 35819730

Brito V*, Montalban E, Pupak A, Masana M, Ginés S, Alberch J, Martin C, Girault JA, Giralt A*. Hippocampal Egr1-dependent neuronal ensembles negatively regulate motor learning. J. Neurosci. 2022 Jul 6;42(27): 5346-5360. doi: 10.1523/ JNEUROSCI. 2258-21.2022. Epub 2022 May 24. * co-correspondings. PMID: 35610044

Matute-Blanch C, Brito V, Midaglia L, Villar LM, Garcia-Diaz Barriga G, Guzman de la Fuente A, Borrás E, Fernández-García S, Calvo-Barreiro L, Miguez A, Costa-Frossard L, Pinteac R, Sabidó E, Alberch J, Fitzgerald DC, Montalban X, Comabella M. Inflammation in multiple sclerosis induces a specific reactive astrocyte state driving non-cell-autonomous neuronal damage.Clin Transl Med. 2022 May;12(5):e837. doi: 10.1002/ ctm2.837. PMID: 35538884

García-Serra S, Radosevic M, Pupak A, Brito V, Ríos J, Aguilar E, Maudes E, Ariño H, Spatola M,  Mannara F, Pedreno M, Joubert B, Ginés S, Planagumà P, and Dalmau J.  Placental transfer of NMDAR antibodies causes reversible alterations in mice. Neurology, Neuroimmunol & Neuroinflam. 2021 Jan; 8(1): e915. Published online 2020 Nov 10. doi: 10.1212/ NXI.0000000000000915. PMC7713722

Sancho-Balsells A, Brito V, Fernández B, Pardo M, Straccia M, Ginés S, Alberch J, Hernández I, Arranz B, Canals JM, Giralt A. A Lack of Helios During Neural Development Induces Adult Schizophrenia-Like Behaviors Associated With Aberrant Levels of the TRIF-Recruiter Protein WDFY1. Front Cell Neurosci. doi: 10.3389/ fncel.2020.00093. eCollection 2020 (IF: 3,921) PMID: 32477064

Giralt A, Brito V, Pardo M, Rubio SE, Marion-Poll L, Martín-Ibáñez R, Zamora-Moratalla A, Bosch C, Ballesteros JJ, Blasco E, García-Torralba A, Pascual M, Pumarola M, Alberch J, Ginés S, Martín ED, Segovia J, Soriano E, Canals JM. Helios modulates the maturation of a CA1 neuronal subpopulation required for spatial memory formation. Exp Neurol. 2020 Jan;323:113095. doi: 10.1016/j.expneurol.2019. 113095 (IF:4.562)

Comella Bolla A, Valente T, Miguez A, Brito V, Gines S, Solà C, Straccia M, Canals JM. CD200 is up-regulated in R6/1 transgenic mouse model of Huntington's disease. PLoS One. 2019 Dec 2;14(12):e0224901. doi: 10.1371/ journal.pone. 0224901 (IF: 2,776) PMID: 31790427

Brito V, Giralt A, Castañé A, Massana M, Alberch J and Ginés S. Cdk5 dysfunction contributes to depressive-like behaviors in Huntington´s Disease by altering the phospho-DARPP-32 status in the nucleus accumbens. Biol Psychiatry. 2019 Aug 1;86(3): 196-207. doi: 10.1016/ j.biopsych. 2019.03.001 (IF: 11,982) PMID: 31060804

Montalban E, Al-Massadi O, Sancho-Balsells A, Brito V, de Pins B, Alberch J, Ginés S, Girault JA, Giralt A. Pyk2 in the amygdala modulates chronic stress sequelae via PSD-95-related micro-structural changes. Transl Psychiatry. Jan 15; 9(1):3. 2019 (IF: 4.691) PMID: 30664624

Suelves Nuria; Miguez Andres; Lopez-Benito Saray; García-Díaz Barriga Gerardo; Giralt Albert; Alvarez-Periel Elena; Arevalo Juan Carlos; Alberch Jordi; Gines Silvia; Brito Veronica. Early downregulation of p75NTR by genetic and pharmacological approaches delays the onset of motor deficits and striatal dysfunction in Huntington´s disease mice. Molecular neurobiology. DOI: 10.1007/ s12035-018-1126-5. 2019 (IF: 5,076) PMID: 29804232

Alvarez-Periel E, Puigdellívol M, Brito V, Plattner F, Bibb JA, Alberch J, Ginés S. Cdk5 Contributes to Huntington's Disease Learning and Memory Deficits via Modulation of Brain Region-Specific Substrates. Mol Neurobiol. Aug;55(8): 6250-6268. doi: 10.1007/ s12035-017-0828-4. 2018 (IF: 5,076) PMID: 29288339

López-Benito Saray; Sánchez-Sánchez Julia; Brito Veronica; Calvo Laura; Torres-Valle Maria; Palko Mary Ellen; Vicente-García Cristina; Fernandez-Fernandez Seila; Bolaños Juan; Gines Silvia; Tessarollo Lino; Lisa Silvia; Arevalo Juan Carlos. Regulation of BDNF release by ARMS/Kidins220 through modulation of Synaptotagmin-IV levels. Journal of Neuroscience. Jun 6;38(23):5415-5428. doi: 10.1523/JNEUROSCI.1653-17. 2018 (IF: 5.988) PMID: 29769266

Illa M, Brito V, Pla L, Eixarch E, Arbat-Plana A, Batallé D, Muñoz-Moreno E, Crispi F, Udina E, Figueras F, Ginés S, Gratacós E. Early Environmental Enrichment Enhances Abnormal Brain Connectivity in a Rabbit Model of Intrauterine Growth Restriction. Fetal Diagn Ther. 2018;44 (3):184-193. doi: 10.1159/000481171. 2018 (IF: 1,8) PMID: 29020672

Giralt A, Brito V, Chevy Q, Simonnet C, Otsu Y, Cifuentes-Díaz C, de Pins B, Coura R, Alberch J, Ginés S, Poncer JC, Girault JA. Pyk2 modulates hippocampal excitatory synapses and contributes to cognitive deficits in a Huntington's disease model. Nat Comm. May 2017. 30;8:15592. doi: 10.1038/ncomms15592. (IF: 12,124). PMID: 28555636

Brito V, Giralt A, Enriquez-Barreto L, Puigdellívol M, Suelves N, Zamora-Moratalla A, Ballesteros JJ, Martín ED, Dominguez-Iturza N, Morales M, Alberch J, Ginés S. Neurotrophin receptor p75NTR mediates Huntington's disease-associated synaptic and memory dysfunction. J Clin Invest 124(10):4411-28. doi: 10.1172/JCI74809. Epub 2014 Sep 2. (IF: 13,215). PMID: 25180603

Brito V, Gines S. p75NTR in Huntington's disease: beyond the basal ganglia. Oncotarget. 5;7(1):1-2. 2016. doi: 10.18632/ oncotarget.6646. (IF: 6,368) Editorial Letter. PMID: 26700963

Miguez A, García-Díaz Barriga G, Brito V, Straccia M, Giralt A, Ginés S, Canals JM, Alberch J. Hum Mol Genet. 1;24 (17):4958-70. 2015 (IF: 6,393)

Puigdellivol M, Cherubini M, Brito V, Giralt A, Suelves N, Zamora-Moratalla A, Martin E. Eipper B, Alberch J, Gines S. A role for Kalirin-7 in .corticostriatal synaptic dysfunction in Huntington’s disease. Hum Mol Genet Dec 20; 24(25): 7265-85. doi: 10.1093/ hmg/ddv426. Epub 2015 Oct 12. 2015  (IF: 6,393). PMID: 26464483

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