title: G2019S LRRK2 mutant fibroblasts from Parkinson's disease patients show increased sensitivity to neurotoxin 1-methyl-4-phenylpyridinium dependent of autophagy.
abstract: Parkinson's disease (PD) is a neurodegenerative disorder of unknown etiology. It is considered as a multifactorial disease dependent on environmental and genetic factors. Deregulation in cell degradation has been related with a significant increase in cell damage, becoming a target for studies on the PD etiology. In the present study, we have characterized the parkinsonian toxin 1-methyl-4-phenylpyridinium ion (MPP(+))-induced damage in fibroblasts from Parkinson's patients with the mutation G2019S in leucine-rich repeat kinase 2 protein (LRRK2) and control individuals without this mutation. The results reveal that MPP(+) induces mTOR-dependent autophagy in fibroblasts. Moreover, the effects of caspase-dependent cell death to MPP(+) were higher in cells with the G2019S LRRK2 mutation, which showed basal levels of autophagy due to the G2019S LRRK2 mutation (mTOR-independent). The inhibition of autophagy by 3-methyladenine (3-MA) treatment reduces these sensitivity differences between both cell types, however, the inhibition of autophagosome-lysosome fusion by bafilomycin A1 (Baf A1) increases these differences. This data confirm the importance of the combination of genetic and environmental factors in the PD etiology. Thereby, the sensitivity to the same damage may be different in function of a genetic predisposition, reason why individuals with certain mutations can develop some early-onset diseases, such as individuals with G2019S LRRK2 mutation and PD.
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Departamento de Bioquímica y Biología Molecular y Genética, F. Enfermería y T.O., Universidad de Extremadura, CP 10003 Cáceres, Spain.
authors.forename: Sokhna M S
authors.initials: SM
authors.lastname: Yakhine-Diop
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Departamento de Bioquímica y Biología Molecular y Genética, F. Enfermería y T.O., Universidad de Extremadura, CP 10003 Cáceres, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Bravo-San Pedro
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Departamento de Bioquímica y Biología Molecular y Genética, F. Enfermería y T.O., Universidad de Extremadura, CP 10003 Cáceres, Spain.
authors.forename: Rubén
authors.initials: R
authors.lastname: Gómez-Sánchez
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Departamento de Bioquímica y Biología Molecular y Genética, F. Enfermería y T.O., Universidad de Extremadura, CP 10003 Cáceres, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Pizarro-Estrella
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Departamento de Bioquímica y Biología Molecular y Genética, F. Enfermería y T.O., Universidad de Extremadura, CP 10003 Cáceres, Spain.
authors.forename: Mario
authors.initials: M
authors.lastname: Rodríguez-Arribas
authors.affiliation: Departamento de Anatomia y Embriologia Humana, Facultad de Medicina, Universidad de Extremadura, 06071 Badajoz, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Climent
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Department of Neurology, Hospital Donostia, San Sebastian, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Aiastui
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Cell Culture Plataform/Neuroscience Area of Health Reseach Biodonostia Institute, Donostia Universitary Hospital, San Sebastián, Spain; Department of Neurology, Hospital Donostia, San Sebastian, Spain; Ilundain Fundazioa, San Sebastian, Spain; Department of Neurosciences, University of the Basque Country UPV-EHU, San Sebastián, Spain.
authors.forename: Adolfo
authors.initials: A
authors.lastname: López de Munain
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Departamento de Bioquímica y Biología Molecular y Genética, F. Enfermería y T.O., Universidad de Extremadura, CP 10003 Cáceres, Spain. Electronic address: jfuentes@unex.es.
authors.forename: José M
authors.initials: JM
authors.lastname: Fuentes
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Departamento de Bioquímica y Biología Molecular y Genética, F. Enfermería y T.O., Universidad de Extremadura, CP 10003 Cáceres, Spain. Electronic address: rosapolo@unex.es.
authors.forename: Rosa A
authors.initials: RA
authors.lastname: González-Polo
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects*; D016022:Case-Control Studies; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D018942:Macrolides / Q000494:pharmacology; D009154:Mutation; D010300:Parkinson Disease / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014162:Transfection
chemical_list: D018942:Macrolides; C025946:3-methyladenine; C040929:bafilomycin A1; C546842:MTOR protein, human; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D020169:Caspases; D000225:Adenine; D015655:1-Methyl-4-phenylpyridinium
keywords: Autophagy; Cell death; LRRK2; Neurotoxin; Parkinson’s disease