Neuronal dysfunction and neurodegeneration in Huntington’s disease (Neuron-glia crosstalk). PI. Sílvia Ginés Padrós

Presentation

The aim of the team is to identify the molecular mechanisms underlying Huntington´s Disease (HD) pathology, a rare inherited autosomal dominant neurodegenerative disorder that progressively affects the individual´s motor, cognitive and affective functions. Despite its well-defined monogenic nature, HD pathogenesis is incredibly complex and the exact mechanism of disease remains still unclear. To answer this question, intensive research efforts have been focused on neuronal activities, properties and circuits. However, astrocyte signalling and metabolism is highly integrated with that of neurons. Therefore, we hypothesize that HD pathology is not a neuron-autonomous event but a failure of neuron-glia communication and in particular a deregulation of the crosstalk between neurons and astrocytes. This may then explain why current treatments mostly focused on neuronal functions have failed to halt HD progression .


Sílvia Ginés Padrós 

Principal Investigator 

silviagines@ub.edu

 

 

 

Nadia di Franco 

Postdoctoral researcher

nadia.difranco@ub.edu

 

 

Laura Celina López Molina 

Predoctoral student

laura.lopezmo12@ub.edu 

 

 

Marc Espina Cortés 

Predoctoral student

marcespina@ub.edu 

 

 


Alba Pereda Velarde 

TFM student 

aperedve@gmail.com 

Though the cardinal symptom of HD is motor disturbances manifested as involuntary movements, cognitive decline is another main symptom that can manifest long before the first motor deficits appear, being the most frequent complaint reported by HD patients. We hypothesize that both striatal-dependent motor deficits and hippocampal-dependent cognitive disturbances may involve and aberrant crosstalk between neurons and astrocytes leading to neuronal dysfunction and degeneration.  

To address this question the team develops the following research lines: 

  • Neuron-astrocyte crosstalk: Mitophagy and transmitophagy in cell specific population

We aim to analyze mitochondria population (dynamics, metabolism, proteomics) with a cell-specific perspective by considering that HD mutation may differentially affects mitochondria in striatal, hippocampal neurons and in non-reactive vs reactive astrocytes. To this aim we take advantage of novel mouse models that allow cell-specific labeling of mitochondria to get new insights into the mitochondrial dysfunction in HD and the contribution to the selective cell-type HD vulnerability. 

  • Neuron-astrocyte crosstalk: Gliotransmitters and synaptic plasticity

We hypothesize that synaptic disturbances and memory deficits in HD will involve not only mutant huntingtin-induced neuronal dysfunction, but also functional alterations in astrocytes, that, in turn, will compromise neuron-astrocyte communication. We propose to dissect the role of gliotransmitters in the synaptic plasticity and cognitive impairments found in HD. We will use well established HD mouse models to evaluate the role of the neuron-astrocyte crosstalk in the hippocampus and the association with hippocampal-dependent memory and learning problems in HD. 

Techniques:

  • Research models: cell lines, primary neuronal and glial cultures, human iPSCs derived neurons and astrocytes, HD mouse models, human samples. 
  • Microscopy: immunohistochemistry, immunofluorescence confocal and live imaging 
  • Biochemistry, Molecular and cell biology: RT-PCR, viral transduction, transfection, immunoprecipitation, ELISA, FACS, Western Blot, cell metabolism 
  • Mice behavioral tests: Rotarod, NORT, NOLT, Morris water maze, Fear conditioning, Tail suspension, sucrose preference test. 
  • In vivo: viral vectors delivery, stereotaxic surgery… 

  • Astrocytes at the hub of neuronal dysfunction in Huntington´s disease: Dissecting the role of ARMS/kidins 220 on astrocyte secretome

European Huntington´s Disease Network (EHDN-1130_201217)
2021-2022. 50.000 €
PI: Sílvia Ginés
Universitat de Barcelona

  • Gliotransmitters and cannabinoid receptors at the hub of cognitive and synaptic plasticity impairments in Huntington's disease.

La Marató de TV3 (30_C_20200310_1149)
2021-2023. 319.708,75 €.
Project Coordinator: Sílvia Ginés
Universitat de Barcelona

  • Transmitophagy between astrocytes and neurons: A new step of neuro-glia crosstalk in Huntington´s disease

Ministerio de Ciencia, Innovación y Universidades (RTI2018-094374-B-I00)
2018-2021. 181.500 €
PI: Sílvia Ginés
Universitat de Barcelona

  • Interacción CB1R-GRP78: ¿Un nuevo mecanismo regulador de la actividad neurprotectora de los cannabinoides?

CIBERNED (CNV-198PRF-739)
2019-2021. 190.400 €
Project Coordinator: Manuel Guzman
Subproject Principal Investigator: Sílvia Ginés 50.000 €
Universitat de Barcelona

  • Non-invasive dynamic neural control by laser-based technology

EUUN-European Union (NEUROPA-863214)
2020-2022. 451.070 €
Investigator: Sílvia Ginés
Universitat de Barcelona

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

Huntington´s Disease Society of America
2017-2018. 75.000 $
Investigator: Sílvia Ginés
Universitat de Barcelona

  • Cdk5 como nueva diana terapéutica y biomarcador del trastorno depresivo en la enfermedad de Huntington

MINECO (SAF2015-67474-R)
2016-2018. 217.800 €
PI: Sílvia Ginés
Universitat de Barcelona

  • Dual therapeutic benefits of isotype-selective HDAC inhibition in Huntington´s disease

European Huntington´s Disease Network (EHDN-1619-14)
2015-2016. 50.000 €
Co-principal Investigator: Sílvia Ginés
Universitat de Barcelona and NUI Galway University

  • Cdk5 a therapeutic target for synaptic and cognitive deficits in Huntington disease

Fundación Ramón Areces (CIVP16A1842)
2012-2015. 84.435 €
PI: Sílvia Ginés
Universitat de Barcelona

  • Cdk5 a potential therapeutic target for synaptic and cognitive deficits in Huntington´s Disease

MINECO (SAF2012-39142)
2012-2015 152.100 €
PI: Sílvia Ginés
Universitat de Barcelona

For more information for PI publications click in the link:
ORCID: https://orcid.org/0000-0002-9479-8185
ResearcherID: http://www.researcherid.com/rid/L-1943-2015
Scopus Author ID:https://www.scopus.com/authid/detail.uri?authorId=6602935864

 

Martín-Flores N, Pérez-Sisqués L, Creus-Muncunill J, Masana M, Ginés S, Alberch J, Pérez-Navarro E, Malagelada C. Synaptic RTP801 contributes to motor-learning dysfunction in Huntington's disease. Cell Death Dis.2020 Jul 30;11(7):569. doi: 10.1038/s41419-020-02775-5. PMID: 32732871

Cherubini M, Lopez-Molina L, Gines S. Mitochondrial fission in Huntington's disease mouse striatum disrupts ER-mitochondria contacts leading to disturbances in Ca2+ efflux and Reactive Oxygen Species (ROS) homeostasis. Neurobiol Dis. 2020 Mar;136:104741. doi: 10.1016/ j.nbd. 2020.104741. Epub 2020 Jan 10. PMID: 31931142

Moreno-Delgado D, Puigdellívol M, Moreno E, Rodríguez-Ruiz M, Botta J, Gasperini P, Chiarlone A, Howell LA, Scarselli M, Casadó V, Cortés A, Ferré S, Guzmán M, Lluís C, Alberch J, Canela EI, *Ginés S, *McCormick PJ. Modulation of dopamine D1 receptors via histamine H3 receptors is a novel therapeutic target for Huntington's disease. Elife. 2020 Jun 9;9: e51093. doi: 10.7554/ eLife.51093. Co-corresponding author. PMID: 32513388

Brito V, Giralt A, Masana M, Royes A, Espina M, Sieiro E, Alberch J, Castañé A, Girault JA, Ginés S. Cyclin-Dependent Kinase 5 Dysfunction Contributes to Depressive-like Behaviors in Huntington's Disease by Altering the DARPP-32 Phosphorylation Status in the Nucleus Accumbens. Biol Psychiatry. 2019 Aug 1;86(3):196-207. doi: 10.1016/ j.biopsych. 2019.03.001. Epub 2019 Mar 13. PMID: 31060804

de Pins B, Cifuentes-Díaz C, Farah AT, López-Molina L, Montalban E, Sancho-Balsells A, López A, Ginés S, Delgado-García JM, Alberch J, Gruart A, Girault JA, Giralt A.Conditional BDNF Delivery from Astrocytes Rescues Memory Deficits, Spine Density, and Synaptic Properties in the 5xFAD Mouse Model of Alzheimer Disease. J Neurosci. 2019 Mar 27;39(13):2441-2458. doi: 10.1523/ JNEUROSCI. 2121-18.2019. Epub 2019 Jan 30. PMID: 30700530

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. 2019 Jan 15;9(1):3. doi: 10.1038/ s41398-018-0352-y. PMID: 30664624

Suelves N, Miguez A, López-Benito S, Barriga GG, Giralt A, Alvarez-Periel E, Arévalo JC, Alberch J, Ginés S, Brito V. Early Downregulation of p75NTR by Genetic and Pharmacological Approaches Delays the Onset of Motor Deficits and Striatal Dysfunction in Huntington's Disease Mice. Mol Neurobiol. 2019 Feb;56(2):935-953. doi: 10.1007/ s12035-018- 1126-5. Epub 2018 May 27. PMID: 29804232

Giralt A, de Pins B, Cifuentes-Díaz C, López-Molina L, Farah AT, Tible M, Deramecourt V, Arold ST, Ginés S, Hugon J, Girault JA. PTK2B/Pyk2 overexpression improves a mouse model of Alzheimer's disease. Exp Neurol. 2018 Sep;307:62-73. doi: 10.1016 /j.expneurol. 2018.05.020. Epub 2018 May 24. PMID: 29803828

López-Benito S, Sánchez-Sánchez J, Brito V, Calvo L, Lisa S, Torres-Valle M, Palko ME, Vicente-García C, Fernández-Fernández S, Bolaños JP, Ginés S, Tessarollo L, Arévalo JC. Regulation of BDNF Release by ARMS/Kidins220 through Modulation of Synaptotagmin-IV Levels. J Neurosci. 2018 Jun 6;38(23): 5415-5428. doi: 10.1523 JNEUROSCI.1653-17.2018. Epub 2018 May 16. PMID: 29769266

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. 2018 Aug;55(8):6250-6268. doi: 10.1007/ s12035-017-0828-4. Epub 2017 Dec 29. PMID: 29288339

Cariulo C, Azzollini L, Verani M, Martufi P, Boggio R, Chiki A, Deguire SM, Cherubini M, Gines S, Marsh JL, Conforti P, Cattaneo E, Santimone I, Squitieri F, Lashuel HA, Petricca L, Caricasole A. Phosphorylation of huntingtin at residue T3 is decreased in Huntington's disease and modulates mutant huntingtin protein conformation. Proc Natl Acad Sci U S A. 2017 Dec 12;114(50): E10809-E10818. doi: 10.1073/ pnas.1705372114. Epub 2017 Nov 21. PMID: 29162692

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. Epub 2017 Oct 12. PMID: 29020672

Suelves N, Kirkham-McCarthy L, Lahue RS, Ginés S. A selective inhibitor of histone deacetylase 3 prevents cognitive deficits and suppresses striatal CAG repeat expansions in Huntington's disease mice. Sci Rep. 2017 Jul 20;7(1):6082. doi: 10.1038/ s41598- 017-05125-2. PMID: 28729730

Daldin M, Fodale V, Cariulo C, Azzollini L, Verani M, Martufi P, Spiezia MC, Deguire SM, Cherubini M, Macdonald D, Weiss A, Bresciani A, Vonsattel JG, Petricca L, Marsh JL, Gines S, Santimone I, Marano M, Lashuel HA, Squitieri F, Caricasole A. Polyglutamine expansion affects huntingtin conformation in multiple Huntington's disease models. Sci Rep. 2017 Jul 11;7(1):5070. doi: 10.1038/ s41598-017- 05336-7. PMID: 28698602

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 Commun. 2017 May 30;8:15592. doi: 10.1038/ ncomms15592. PMID: 28555636

Saavedra A, Fernández-García S, Cases S, Puigdellívol M, Alcalá-Vida R, Martín-Flores N, Alberch J, Ginés S, Malagelada C, Pérez-Navarro E. Chelerythrine promotes Ca2+-dependent calpain activation in neuronal cells in a PKC-independent manner. Biochim Biophys Acta Gen Subj. 2017 Apr;1861(4):922-935. doi: 10.1016 / j.bbagen. 2017.01.021. Epub 2017 Jan 24. PMID: 28130160

Moreno E, Chiarlone A, Medrano M, Puigdellívol M, Bibic L, Howell LA, Resel E, Puente N, Casarejos MJ, Perucho J, Botta J, Suelves N, Ciruela F, Ginés S, Galve-Roperh I, Casadó V, Grandes P, Lutz B, Monory K, Canela EI, Lluís C, McCormick PJ, Guzmán M. Singular Location and Signaling Profile of Adenosine A2A-Cannabinoid CB1 Receptor Heteromers in the Dorsal Striatum. Neuropsychopharmacology. 2018 Apr;43(5):964-977. doi: 10.1038/ npp. 2017.12. Epub 2017 Jan 19. PMID: 28102227

Cherubini M, Ginés S. Mitochondrial fragmentation in neuronal degeneration: Toward an understanding of HD striatal susceptibility. Biochem Biophys Res Commun. 2017 Feb 19;483(4):1063-1068. doi: 10.1016 / j.bbrc. 2016.08. 042. Epub 2016 Aug 8. Review. PMID: 27514446

Brito V, Ginés S. p75NTR in Huntington's disease: beyond the basal ganglia. Oncotarget. 2016 Jan 5;7(1):1-2. doi: 10.18632/ oncotarget. 6646. No abstract available. PMID: 26700963

Pont L, Benavente F, Jaumot J, Tauler R, Alberch J, Ginés S, Barbosa J, Sanz-Nebot V. Metabolic profiling for the identification of Huntington biomarkers by on-line solid-phase extraction capillary electrophoresis mass spectrometry combined with advanced data analysis tools. Electrophoresis. 2016 Mar;37(5-6):795-808. doi: 10.1002/ elps. 201500378. Epub 2016 Feb 8. PMID: 26685060

Puigdellívol M, Cherubini M, Brito V, Giralt A, Suelves N, Ballesteros J, Zamora-Moratalla A, Martín ED, Eipper BA, Alberch J, Ginés S. A role for Kalirin-7 in corticostriatal synaptic dysfunction in Huntington's disease. Hum Mol Genet. 2015 Dec 20;24(25):7265-85. doi: 10.1093/ hmg/ddv 426. Epub 2015 Oct 12. PMID: 26464483

Saavedra A, Puigdellívol M, Tyebji S, Kurup P, Xu J, Ginés S, Alberch J, Lombroso PJ, Pérez-Navarro E. BDNF Induces Striatal-Enriched Protein Tyrosine Phosphatase 61 Degradation Through the Proteasome. Mol Neurobiol. 2016 Aug;53(6):4261-4273. doi: 10.1007/ s12035-015- 9335-7. Epub 2015 Jul 30. PMID: 26223799

Cherubini M, Puigdellívol M, Alberch J, Ginés S. Cdk5-mediated mitochondrial fission: A key player in dopaminergic toxicity in Huntington's disease. Biochim Biophys Acta. 2015 Oct;1852(10 Pt A):2145-60. doi: 10.1016 / j.bbadis. 2015.06. 025. Epub 2015 Jul 2. PMID: 26143143

Fernández-Nogales M, Hernández F, Miguez A, Alberch J, Ginés S, Pérez-Navarro E, Lucas JJ. Decreased glycogen synthase kinase-3 levels and activity contribute to Huntington's disease. Hum Mol Genet. 2015 Sep 1;24(17): 5040-52. doi: 10.1093/hmg/ ddv224. Epub 2015 Jun 16. PMID: 26082469

Miguez A, García-Díaz Barriga G, Brito V, Straccia M, Giralt A, Ginés S, Canals JM, Alberch J. Fingolimod (FTY720) enhances hippocampal synaptic plasticity and memory in Huntington's disease by preventing p75NTR up-regulation and astrocyte-mediated inflammation. Hum Mol Genet. 2015 Sep 1;24(17):4958-70. doi: 10.1093/ hmg/ddv218. Epub  2015 Jun 10. PMID: 26063761

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 p75(NTR) mediates Huntington's disease-associated synaptic and memory dysfunction. J Clin Invest. 2014 Oct;124(10): 4411-28. doi: 10.1172/ JCI74809. Epub 2014 Sep 2. PMID: 25180603

  • Offers from the University of Barcelona:

Work UB

  • Offers from the Research Group:

Open position for a predocoral students. The team is seeking an enthusiastic and motivated predoctoral candidate to apply to 3-year predoctoral full-time contract “Ayuda FI Generalitat de Catalunya 2022". 

Selection process 

To apply for a place, please send the following documentation: 

  1. Curriculum Vitae 
  2. Brief explanatory letter of previous experience and interest in the proposed research area 

Send documentation via e-mail to silviagines@ub.edu before October 10th, 2022. 

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