The Small GTPase RAC1/CED-10 Is Essential in Maintaining Dopaminergic Neuron Function and Survival Against a-Synuclein-Induced Toxicity.
Por:
Kim H, Calatayud Aristoy C, Guha S, Fernández-Carasa I, Berkowitz L, Carballo-Carbajal I, Ezquerra M, Fernández-Santiago R, Kapahi P, Raya Á, Miranda-Vizuete A, Lizcano JM, Vilà-Ubach M, Caldwell KA, Caldwell GA, Consiglio A and Dalfo E
Publicada:
1 sep 2018
Ahead of Print:
10 feb 2018
Resumen:
Parkinson's disease is associated with intracellular a-synuclein accumulation and ventral midbrain dopaminergic neuronal death in the Substantia Nigra of brain patients. The Rho GTPase pathway, mainly linking surface receptors to the organization of the actin and microtubule cytoskeletons, has been suggested to participate to Parkinson's disease pathogenesis. Nevertheless, its exact contribution remains obscure. To unveil the participation of the Rho GTPase family to the molecular pathogenesis of Parkinson's disease, we first used C elegans to demonstrate the role of the small GTPase RAC1 (ced-10 in the worm) in maintaining dopaminergic function and survival in the presence of alpha-synuclein. In addition, ced-10 mutant worms determined an increase of alpha-synuclein inclusions in comparison to control worms as well as an increase in autophagic vesicles. We then used a human neuroblastoma cells (M17) stably over-expressing alpha-synuclein and found that RAC1 function decreased the amount of amyloidogenic alpha-synuclein. Further, by using dopaminergic neurons derived from patients of familial LRRK2-Parkinson's disease we report that human RAC1 activity is essential in the regulation of dopaminergic cell death, alpha-synuclein accumulation, participates in neurite arborization and modulates autophagy. Thus, we determined for the first time that RAC1/ced-10 participates in Parkinson's disease associated pathogenesis and established RAC1/ced-10 as a new candidate for further investigation of Parkinson's disease associated mechanisms, mainly focused on dopaminergic function and survival against a-synuclein-induced toxicity.
Filiaciones:
Kim H:
Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, 35487, USA
Calatayud Aristoy C:
Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, 08028, L'Hospitalet de Llobregat, Spain
Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, 08908, Spain
Center of Regenerative Medicine in Barcelona (CMRB), Center for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Hospital Duran i Reynals, 08908, L'Hospitalet de Llobregat, Spain
Guha S:
Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA, 94945, USA
Fernández-Carasa I:
Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, 08028, L'Hospitalet de Llobregat, Spain
Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, 08908, Spain
Berkowitz L:
Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, 35487, USA
Carballo-Carbajal I:
Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute-Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), 08035, Barcelona, Spain
Ezquerra M:
Laboratory of Parkinson Disease and Other Neurodegenerative Movement Disorders, Department of Neurology: Clinical and Experimental Research, IDIBAPS - Hospital Clínic de Barcelona, 08036, Barcelona, Spain
Fernández-Santiago R:
Laboratory of Parkinson Disease and Other Neurodegenerative Movement Disorders, Department of Neurology: Clinical and Experimental Research, IDIBAPS - Hospital Clínic de Barcelona, 08036, Barcelona, Spain
Kapahi P:
Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA, 94945, USA
Raya Á:
Center of Regenerative Medicine in Barcelona (CMRB), Center for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Hospital Duran i Reynals, 08908, L'Hospitalet de Llobregat, Spain
Catalan Institution for Research and Advanced Studies (ICREA), 08010, Barcelona, Spain
Miranda-Vizuete A:
Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/ Universidad de Sevilla, 41013, Sevilla, Spain
Lizcano JM:
Department of Biochemistry and Molecular Biology, Institut de Neurociències, Faculty of Medicine, M2, Universitat Autònoma de Barcelona (UAB), Bellaterra Campus, Cerdanyola del Vallés, Barcelona, Spain
Vilà-Ubach M:
Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute-Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), 08035, Barcelona, Spain
Catalan Institution for Research and Advanced Studies (ICREA), 08010, Barcelona, Spain
Department of Biochemistry and Molecular Biology, Institut de Neurociències, Faculty of Medicine, M2, Universitat Autònoma de Barcelona (UAB), Bellaterra Campus, Cerdanyola del Vallés, Barcelona, Spain
Caldwell KA:
Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, 35487, USA
Caldwell GA:
Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, 35487, USA
Consiglio A:
Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, 08028, L'Hospitalet de Llobregat, Spain.
Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, 08908, Spain.
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Spain.
Dalfo E:
Department of Biochemistry and Molecular Biology, Institut de Neurociències, Faculty of Medicine, M2, Universitat Autònoma de Barcelona (UAB), Bellaterra Campus, Cerdanyola del Vallés, Barcelona, Spain.
Faculty of Medicine, University of Vic-Central University of Catalonia (UVic-UCC), Can Baumann, 08500, Vic, Spain.
Open Access
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