RT Journal Article
T1 The Small GTPase RAC1/CED-10 Is Essential in Maintaining Dopaminergic Neuron Function and Survival Against α-Synuclein-Induced Toxicity.
A1 Kim, Hanna
A1 Calatayud, Carles
A1 Guha, Sanjib
A1 Fernandez-Carasa, Irene
A1 Berkowitz, Laura
A1 Carballo-Carbajal, Iria
A1 Ezquerra, Mario
A1 Fernandez-Santiago, Ruben
A1 Kapahi, Pankaj
A1 Raya, Angel
A1 Miranda-Vizuete, Antonio
A1 Lizcano, Jose Miguel
A1 Vila, Miquel
A1 Caldwell, Kim A
A1 Caldwell, Guy A
A1 Consiglio, Antonella
A1 Dalfo, Esther
K1 Alpha-synuclein accumulation
K1 Autophagy impairment
K1 Dopaminergic neurons
K1 Parkinson’s disease
K1 RAC1/ced-10
AB 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.
PB Springer
YR 2018
FD 2018-02-10
LK http://hdl.handle.net/10668/12113
UL http://hdl.handle.net/10668/12113
LA en
NO Kim H, Calatayud C, Guha S, Fernández-Carasa I, Berkowitz L, Carballo-Carbajal I, et al. The Small GTPase RAC1/CED-10 Is Essential in Maintaining Dopaminergic Neuron Function and Survival Against α-Synuclein-Induced Toxicity. Mol Neurobiol. 2018 Sep;55(9):7533-7552.
DS RISalud
RD Apr 10, 2025