The small GTPase RAC1/CED-10 is essential in maintaining dopaminergic neuron function and survival against α-synuclein-induced toxicity

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...

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Detalles Bibliográficos
Autores: Kim, Hanna, Calatayud, Carles|||0000-0003-0032-4198, Guha, Sanjib, Fernandez Carasa, Irene|||0000-0002-8195-3510, Berkowitz, Laura, Carballo-Carbajal, Iria|||0000-0002-4403-8006, Ezquerra, Mario|||0000-0003-3246-6641, Fernández-Santiago, Rubén|||0000-0002-4582-0702, Kapahi, Pankaj, Raya, Ángel|||0000-0003-2189-9775, Miranda Vizuete, Antonio, Lizcano de Vega, José Miguel|||0000-0002-3154-5383, Vila Bover, Miquel|||0000-0002-1352-989X, Caldwell, Kim A., Caldwell, Guy A., Consiglio, Antonella, Dalfo, Esther|||0000-0003-4677-8515
Tipo de recurso: artículo
Fecha de publicación:2018
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:219402
Acceso en línea:https://ddd.uab.cat/record/219402
https://dx.doi.org/urn:doi:10.1007/s12035-018-0881-7
Access Level:acceso abierto
Palabra clave:Parkinson's disease
Dopaminergic neurons
Alpha-synuclein accumulation
Autophagy impairment
RAC1/ced-10
Descripción
Sumario: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.

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