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Instituto de Parasitología y Biomedicina
"López - Neyra"
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[ Staff | Summary of Research | Funding Agencies | Publications | Doctoral Theses | Patents | Teaching]




Laboratory of Molecular and Cellular Neuroscience



Group Leader
    • Sabine Hilfiker      
        email: sabine.hilfiker (@ipb.csic.es)
        Tlf: 958181654



    Staff Research Posdoctoral
    • Elena Fernández Fernández     


    Authorized Staff
    • Cristina García Gento     
    • Pablo Macías Sánchez     

     

    SUMMARY OF RESEARCH


     

    1. Elucidation of the molecular basis of neurotransmitter release and its regulation.

     

    One of our major research goals is to elucidate the molecular mechanisms underlying neurotransmitter release in both normal and pathological states. As a first step towards this goal, we have identified that SNARE complexes, which are the basic machinery enabling vesicle fusion, exist as multimers in solution, and we have shown that such multimerization is important for neurosecretion in vivo. These findings suggest that SNARE complex multimerization may improve the efficiency of vesicle exocytosis in a cooperative manner. We are characterizing these new oligomers using a combination of biochemical and cell biological approaches.









     

    2. Investigation of the pathogenic mechanisms of neurodegenerative diseases.

     

    Another major goal of our research is to elucidate the pathogenic mechanisms of neurodegenerative diseases, specifically Parkinson?s disease. Recent breakthrough in genetic studies has provided clues that mutations in a-synuclein (a synaptic vesicle-associated protein), parkin (an ubiquitin-protein ligase), UCH-L1 (a deubiquitinating enzyme), DJ-1 (a chaperone), PINK1 (a mitochondrial kinase) and LRRK2 (a cytosolic kinase) are involved in the pathogenesis of Parkinson?s disease. We are using an interdisciplinary approach to delineate the molecular pathways by which mutations in these proteins lead to neurodegeneration, and to identify other molecular players in the pathogenic pathways leading to Parkinson?s disease. For example, our recent work provides the first evidence of a molecular mechanism by which the most prominent mutation in LRRK2 acts to increase kinase activity and cytotoxicity. In addition, we are very interested in understanding the role of abnormal vesicular trafficking in Parkinson?s disease. Through our studies, we hope to define new protein targets for understanding and treating Parkinson?s disease and possibly other neurodegenerative diseases as well.









     


    FUNDING AGENCIES LAST 5 YEARS

    - LRRK2 Biology Consortium Program "LRRK2-mediated centrosomal cohesion alterations". PROYECTO, , Ref: MMF_2018, (2018 - 2021).

    - RELACION ENTRE LRRK2 Y EL DEFICIT DE TRAFICO VESICULAR MEDIADO POR RABS EN LA ENFERMEDAD DE PARKINSON. PROYECTO, PN2017 - PROY I+D+I - PRG. RETOS DE LA SOCIEDAD, Ref: SAF2017-89402-R, (2018 - 2020).

    - Kinase-activity-mediated centrosomal alterations in LRRK2-PD and sporadic PD-patient-derived cells and link to altered Rab protein-locaization/Phosphorylation. PROYECTO, Michael J. Fox Foundation for Parkinson`s Research 2017, Ref: MJFF_2017, (2017 - 2018).

    - LRRK2-mediated endolysosomal alterations:mechanistic insights and validation as pharmacodynamic readout for kinase inhibitor studies. PROYECTO, , Ref: MJFF_2016, (2016 - 2018).

    - PS-derived neural presucros cells to study mechanisms and identify modulators of Parkinson¿s disease.. PROYECTO, F. BBVA-AYUDAS A PROYECTOS DE INVESTIGACIÓN 2014, Ref: 201422031, (2014 - 2018).

     

     

    PUBLICATIONS LAST 5 YEARS

    -Fdez, E; Madero-Pérez, J; Lara Ordóñez, A.J; Naaldijk, Y; Fasiczka, R; Aiastui, A; Ruiz Martínez, J; López de Munain, A; Cowley, S.A; Wade-Martins, R; Hilfiker, S, Pathogenic LRRK2 regulates centrosome cohesion via Rab10/RILPL1-mediated CDK5RAP2 displacement, iScience, 2022, Vol. 25: 1044766-104476, ARTÍCULO, Id:892848

    -Ordóñez, A.J.L.; Fasiczka, R.; Naaldijk, Y.; Hilfiker, S., Rab GTPases in Parkinson’s disease: a primer, Essays in Biochemistry, 2021, Vol. 65: 961-974, ARTÍCULO DE REVISIÓN, Id:868210

    -Rivero-Ríos, P.; Romo-Lozano, M.; Fernández, B.; Fdez, E.; Hilfiker, S., Distinct Roles for RAB10 and RAB29 in Pathogenic LRRK2-Mediated Endolysosomal Trafficking Alterations, Cells, 2020, Vol. 9: , ARTÍCULO, Id:812239

    -Rivero-Ríos, P.; Romo-Lozano, M.; Fasiczka, R.; Naaldijk, Y.; Hilfiker, S., LRRK2-Related Parkinson’s Disease Due to Altered Endolysosomal Biology With Variable Lewy Body Pathology: A Hypothesis, Frontiers in Neuroscience, 2020, Vol. 14: 556, ARTÍCULO DE REVISIÓN, Id:809748

    -Lara Ordónez, A.J.; Fernández, B.; Fdez, E.; Romo-Lozano, M.; Madero-Pérez, J.; Lobbestael, E.; Baekelandt, V.; Aiastui, A.; López de Munaín, A.; Melrose, H.L.; Civiero, L.; Hilfiker, S., RAB8, RAB10 and RILPL1 contribute to both LRRK2 kinase-mediated centrosomal cohesion and ciliogenesis deficits, Human Molecular Genetics, 2019, Vol. 28: 3552-3568, ARTÍCULO, Id:781631

    -Rivero-Ríos, P.; Romo-Lozano, M.; Madero-Pérez, J.; Thomas, A.P.; Biosa, A.; Greggio, E.; Hilfiker, S., The G2019S variant of leucine-rich repeat kinase 2 (LRRK2) alters endolysosomal trafficking by impairing the function of the GTPase RAB8A, Journal of Biological Chemistry, 2019, Vol. 294: 4738-4758, ARTÍCULO, Id:748045

    -Madero-Pérez, J.; Fernández, B.; Lara Ordóñez, A.J.; Fdez, E.; Lobbestael, E.; Baekelandt, V.; Hilfiker, S., RAB7L1-mediated relocalization of LRRK2 to the golgi complex causes centrosomal deficits via RAB8A, Frontiers in Molecular Neuroscience, 2018, Vol. 11: 417, ARTÍCULO, Id:735371

    -Madero-Pérez, J.; Fdez, E.; Fernández, B.; Lara Ordóñez, A.J.; Blanca Ramírez, M.; Gómez-Suaga, P.; Waschbüsch, D.; Lobbestael, E.; Baekelandt, V.; Nairn, A.C.; Ruiz-Martínez, J.; Aiastui, A.; López De Munain, A.; Lis, P.; Comptdaer, T.; Taymans, J.M.; Chartier-Harlin, M.C.; Beilina, A.; Gonnelli, A.; Cookson, M.R.; Greggio, E.; Hilfiker, S., Parkinson disease-associated mutations in LRRK2 cause centrosomal defects via Rab8a phosphorylation, Molecular Neurodegeneration, 2018, Vol. 13: 1-3, ARTÍCULO, Id:715230


     

     

    DOCTORAL THESES LAST 5 YEARS

     

    2021

    Antonio Jesús Lara Ordóñez

    Molecular mechanisms underlying LRRK2-mediated centrosomal cohesion deficits as biomarker for Parkinson?s disease

    IPBLN CSIC

     

     
    2019

    Pilar Rivero Ríos

    Mechanisms underlying endolysosomal deficits mediated by the Parkinson's disease-related kinase LRRK2

    IPBLN CSIC

     

     
    2018

    Jesús Madero Pérez

    Centrosomal defects caused by the Parkinson´s disease associated protein kinase LRRK2 and Rab proteins

    IPBLN CSIC

     

     

     

     


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