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Title: The Small GTPase RAC1/CED-10 Is Essential in Maintaining Dopaminergic Neuron Function and Survival Against alpha-Synuclein-Induced Toxicity
Author: Kim, Hanna
Calatayud Aristoy, Carles
Guha, Sanjib
Fernandez-Carasa, Irene
Berkowitz, Laura
Carballo Carbajal, Iria
Ezquerra, Mario
Fernandez Santiago, Ruben
Kapahi, Pankaj
Raya Chamorro, Ángel
Miranda Vizuete, Antonio
Miguel Lizcano, Jose
Vila, Miquel
Caldwell, Kim A.
Caldwell, Guy A.
Consiglio, Antonella
Dalfo, Esther
Keywords: Malaltia de Parkinson
Malalties neurodegeneratives
Parkinson's disease
Neurodegenerative Diseases
Issue Date: 1-Sep-2018
Publisher: Humana Press
Abstract: Parkinson's disease is associated with intracellular α-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 α-synuclein-induced toxicity.
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It is part of: Molecular Neurobiology, 2018, vol. 55, num. 9, p. 7533-7552
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ISSN: 0893-7648
Appears in Collections:Articles publicats en revistes (Patologia i Terapèutica Experimental)
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Articles publicats en revistes (Institut de Biomedicina (IBUB))
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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