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MicroRNA alterations in iPSC-derived dopaminergic neurons from Parkinson disease patients.
Neurobiol Aging. 2018 09; 69:283-291.NA

Abstract

MicroRNA (miRNA) misregulation in peripheral blood has been linked to Parkinson disease (PD) but its role in the disease progression remains elusive. We performed an explorative genome-wide study of miRNA expression levels in dopaminergic neurons (DAn) from PD patients generated by somatic cell reprogramming and induced pluripotent stem cells differentiation. We quantified expression levels of 377 miRNAs in DAn from 3 sporadic PD patients (sPD), 3 leucine-rich repeat kinase 2-associated PD patients (L2PD) (total 6 PD), and 4 healthy controls. We identified differential expression of 10 miRNA of which 5 were upregulated in PD (miR-9-5p, miR-135a-5p, miR-135b-5p, miR-449a, and miR-449b-5p) and 5 downregulated (miR-141-3p, miR-199a-5p, miR-299-5p, miR-518e-3p, and miR-519a-3p). Changes were similar in sPD and L2PD. Integrative analysis revealed significant correlations between miRNA/mRNA expression. Moreover, upregulation of miR-9-5p and miR-135b-5p was associated with downregulation of transcription factors related to the DNA hypermethylation of enhancer elements in PD DAn (FOXA1 and NR3C1). In summary, miRNA changes are associated with monogenic L2PD and sPD and co-occur with epigenetic changes in DAn from PD patients.

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Authors+Show Affiliations

Tolosa E
Department of Neurology, Laboratory of Parkinson Disease and Other Neurodegenerative Movement Disorders, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona (UB), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
Botta-Orfila T
Gene Function and Evolution Group, Centre for Genomic Regulation (CRG), Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain.
Morató X
Departament Patologia i Terapèutica Experimental, Unitat de Farmacologia, Facultat de Medicina, IDIBELL-Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain; Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain.
Calatayud C
Department of Pathology and Experimental Therapeutics, Institute of Biomedicine of the University of Barcelona (IBUB), Bellvitge University Hospital-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
Ferrer-Lorente R
Center of Regenerative Medicine in Barcelona (CMRB), Hospital Duran i Reynals, Hospitalet de Llobregat, Barcelona, Spain; Centre for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain.
Martí MJ
Department of Neurology, Laboratory of Parkinson Disease and Other Neurodegenerative Movement Disorders, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona (UB), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
Fernández M
Department of Neurology, Laboratory of Parkinson Disease and Other Neurodegenerative Movement Disorders, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona (UB), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
Gaig C
Department of Neurology, Laboratory of Parkinson Disease and Other Neurodegenerative Movement Disorders, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona (UB), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Department of Neurology, Multidisciplinary Sleep Unit, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
Raya Á
Center of Regenerative Medicine in Barcelona (CMRB), Hospital Duran i Reynals, Hospitalet de Llobregat, Barcelona, Spain; Centre for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
Consiglio A
Department of Pathology and Experimental Therapeutics, Institute of Biomedicine of the University of Barcelona (IBUB), Bellvitge University Hospital-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain; Department of Pathology and Experimental Therapeutics, Faculty of Medicine, IDIBELL- University of Barcelona, Barcelona, Spain; Department of Molecular and Translational Medicine, University of Brescia and National Institute of Neuroscience, Brescia, Italy. Electronic address: consiglio@ub.es.
Ezquerra M
Department of Neurology, Laboratory of Parkinson Disease and Other Neurodegenerative Movement Disorders, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona (UB), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. Electronic address: ezquerra@clinic.ub.es.
Fernández-Santiago R
Department of Neurology, Laboratory of Parkinson Disease and Other Neurodegenerative Movement Disorders, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona (UB), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. Electronic address: ruben.fernandez.santiago@gmail.com.

MeSH

AdultAgedCell DifferentiationDopaminergic NeuronsDown-RegulationFemaleGene ExpressionGene Expression ProfilingHumansInduced Pluripotent Stem CellsLeucine-Rich Repeat Serine-Threonine Protein Kinase-2MaleMicroRNAsMiddle AgedNeural Stem CellsParkinson DiseaseUp-Regulation

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29935433

Citation

Tolosa, Eduard, et al. "MicroRNA Alterations in iPSC-derived Dopaminergic Neurons From Parkinson Disease Patients." Neurobiology of Aging, vol. 69, 2018, pp. 283-291.
Tolosa E, Botta-Orfila T, Morató X, et al. MicroRNA alterations in iPSC-derived dopaminergic neurons from Parkinson disease patients. Neurobiol Aging. 2018;69:283-291.
Tolosa, E., Botta-Orfila, T., Morató, X., Calatayud, C., Ferrer-Lorente, R., Martí, M. J., Fernández, M., Gaig, C., Raya, Á., Consiglio, A., Ezquerra, M., & Fernández-Santiago, R. (2018). MicroRNA alterations in iPSC-derived dopaminergic neurons from Parkinson disease patients. Neurobiology of Aging, 69, 283-291. https://doi.org/10.1016/j.neurobiolaging.2018.05.032
Tolosa E, et al. MicroRNA Alterations in iPSC-derived Dopaminergic Neurons From Parkinson Disease Patients. Neurobiol Aging. 2018;69:283-291. PubMed PMID: 29935433.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - MicroRNA alterations in iPSC-derived dopaminergic neurons from Parkinson disease patients. AU - Tolosa,Eduard, AU - Botta-Orfila,Teresa, AU - Morató,Xavier, AU - Calatayud,Carles, AU - Ferrer-Lorente,Raquel, AU - Martí,María-José, AU - Fernández,Manel, AU - Gaig,Carles, AU - Raya,Ángel, AU - Consiglio,Antonella, AU - Ezquerra,Mario, AU - Fernández-Santiago,Rubén, Y1 - 2018/05/31/ PY - 2017/03/27/received PY - 2018/05/23/revised PY - 2018/05/24/accepted PY - 2018/6/24/pubmed PY - 2019/5/22/medline PY - 2018/6/24/entrez KW - Dopaminergic neuron (DAn) KW - Leucine-rich repeat kinase 2 (LRRK2) KW - Parkinson disease (PD) KW - Transcription factor (TF) KW - microRNA (miRNA) SP - 283 EP - 291 JF - Neurobiology of aging JO - Neurobiol Aging VL - 69 N2 - MicroRNA (miRNA) misregulation in peripheral blood has been linked to Parkinson disease (PD) but its role in the disease progression remains elusive. We performed an explorative genome-wide study of miRNA expression levels in dopaminergic neurons (DAn) from PD patients generated by somatic cell reprogramming and induced pluripotent stem cells differentiation. We quantified expression levels of 377 miRNAs in DAn from 3 sporadic PD patients (sPD), 3 leucine-rich repeat kinase 2-associated PD patients (L2PD) (total 6 PD), and 4 healthy controls. We identified differential expression of 10 miRNA of which 5 were upregulated in PD (miR-9-5p, miR-135a-5p, miR-135b-5p, miR-449a, and miR-449b-5p) and 5 downregulated (miR-141-3p, miR-199a-5p, miR-299-5p, miR-518e-3p, and miR-519a-3p). Changes were similar in sPD and L2PD. Integrative analysis revealed significant correlations between miRNA/mRNA expression. Moreover, upregulation of miR-9-5p and miR-135b-5p was associated with downregulation of transcription factors related to the DNA hypermethylation of enhancer elements in PD DAn (FOXA1 and NR3C1). In summary, miRNA changes are associated with monogenic L2PD and sPD and co-occur with epigenetic changes in DAn from PD patients. SN - 1558-1497 UR - https://www.unboundmedicine.com/medline/citation/29935433/MicroRNA_alterations_in_iPSC_derived_dopaminergic_neurons_from_Parkinson_disease_patients_ DB - PRIME DP - Unbound Medicine ER -