The Small GTPase RAC1/CED-10 Is Essential in Maintaining Dopaminergic Neuron Function and Survival Against α-Synuclein-Induced Toxicity

• DOI: 10.1007/s12035-018-0881-7
• Publication Date: 2018-02-10T05:34:17Z
• Authors: Hanna Kim; Carles Calatayud; Sanjib Guha; Irene Fernández-C...; Laura Berkowitz; Iria Carballo-Car...; Mario Ezquerra; Rubén Fernández-S...; Pankaj Kapahi; Ángel Raya; Antonio Miranda-V...; Jose Miguel Lizcano; Miquel Vila; Kim A. Caldwell; Guy A. Caldwell; Antonella Consiglio; Esther Dalfo
• Keywords: rac1 GTP-Binding Protein; Parkinson's disease; Dopamine; Dopaminergic neurons; Neuroblastoma; Mesencephalon; alfa-Sinucleína; Malaltia de Parkinson; Inclusion Bodies; 0303 health sciences; RAC1/ced-10; Behavior, Animal; Cell Death; Autophagy impairment; Malalties neurodegeneratives; Microtúbulos; Neurodegenerative Diseases; Parkinson Disease; 16. Peace & justice; Neuroprotection; rac GTP-Binding Proteins; Enfermedad de Parkinson; alpha-Synuclein; Pacientes; Amyloid; Alpha-synuclein accumulation; Alpha-synuclein accumulation; Autophagy impairment; Dopaminergic neurons; Parkinson’s disease; RAC1/ced-10; Cellular and Molecular Neuroscience; Cell Survival; Induced Pluripotent Stem Cells; Autofagia; Patogénesis homeopática; Article; 03 medical and health sciences; Cell Line, Tumor; Autophagy; Neurites; Animals; Humans; Neuritas; Neuronas dopaminérgicas; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Dopaminergic Neurons; Toxicidad; Muerte celular; Alpha-synuclein accumulation, Autophagy impairment, Dopaminergic neurons, Parkinson’s disease, RAC1/ced-10; Citoesqueleto; Sinucleínas; Mutation; Parkinson’s disease; Biomarkers

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.