Investigating the role of mitochondrial dysfunction in the pathogenesis of Parkinsons´s disease using patient-specific derived astrocytes

Programa de Doctorat en Biomedicina

Detalles Bibliográficos
Autor: Fernández Carasa, Irene
Tipo de recurso: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:CBUC, CESCA
Repositorio:TDR. Tesis Doctorales en Red
OAI Identifier:oai:www.tdx.cat:10803/673716
Acceso en línea:http://hdl.handle.net/10803/673716
Access Level:acceso abierto
Palabra clave:Malalties neurodegeneratives
Enfermedades neurodegenerativas
Neurodegenerative Diseases
Malaltia de Parkinson
Enfermedad de Parkinson
Parkinson's disease
Cèl·lules mare
Células madre
Stem cells
Neuròglia
Neuroglia
Citologia
Citología
Cytology
Ciències Experimentals i Matemàtiques
577
id ES_7526b930b14ae42c1075cae13f33400a
oai_identifier_str oai:www.tdx.cat:10803/673716
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Investigating the role of mitochondrial dysfunction in the pathogenesis of Parkinsons´s disease using patient-specific derived astrocytes
title Investigating the role of mitochondrial dysfunction in the pathogenesis of Parkinsons´s disease using patient-specific derived astrocytes
spellingShingle Investigating the role of mitochondrial dysfunction in the pathogenesis of Parkinsons´s disease using patient-specific derived astrocytes
Fernández Carasa, Irene
Malalties neurodegeneratives
Enfermedades neurodegenerativas
Neurodegenerative Diseases
Malaltia de Parkinson
Enfermedad de Parkinson
Parkinson's disease
Cèl·lules mare
Células madre
Stem cells
Neuròglia
Neuroglia
Citologia
Citología
Cytology
Ciències Experimentals i Matemàtiques
577
title_short Investigating the role of mitochondrial dysfunction in the pathogenesis of Parkinsons´s disease using patient-specific derived astrocytes
title_full Investigating the role of mitochondrial dysfunction in the pathogenesis of Parkinsons´s disease using patient-specific derived astrocytes
title_fullStr Investigating the role of mitochondrial dysfunction in the pathogenesis of Parkinsons´s disease using patient-specific derived astrocytes
title_full_unstemmed Investigating the role of mitochondrial dysfunction in the pathogenesis of Parkinsons´s disease using patient-specific derived astrocytes
title_sort Investigating the role of mitochondrial dysfunction in the pathogenesis of Parkinsons´s disease using patient-specific derived astrocytes
dc.creator.none.fl_str_mv Fernández Carasa, Irene
author Fernández Carasa, Irene
author_facet Fernández Carasa, Irene
author_role author
dc.contributor.none.fl_str_mv Consiglio, Antonella
Río Fernández, José Antonio del
Universitat de Barcelona. Facultat de Biologia
dc.subject.none.fl_str_mv Malalties neurodegeneratives
Enfermedades neurodegenerativas
Neurodegenerative Diseases
Malaltia de Parkinson
Enfermedad de Parkinson
Parkinson's disease
Cèl·lules mare
Células madre
Stem cells
Neuròglia
Neuroglia
Citologia
Citología
Cytology
Ciències Experimentals i Matemàtiques
577
topic Malalties neurodegeneratives
Enfermedades neurodegenerativas
Neurodegenerative Diseases
Malaltia de Parkinson
Enfermedad de Parkinson
Parkinson's disease
Cèl·lules mare
Células madre
Stem cells
Neuròglia
Neuroglia
Citologia
Citología
Cytology
Ciències Experimentals i Matemàtiques
577
description Programa de Doctorat en Biomedicina
publishDate 2021
dc.date.none.fl_str_mv 2021
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10803/673716
url http://hdl.handle.net/10803/673716
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 181 p.
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Universitat de Barcelona
publisher.none.fl_str_mv Universitat de Barcelona
dc.source.none.fl_str_mv TDX (Tesis Doctorals en Xarxa)
reponame:TDR. Tesis Doctorales en Red
instname:CBUC, CESCA
instname_str CBUC, CESCA
reponame_str TDR. Tesis Doctorales en Red
collection TDR. Tesis Doctorales en Red
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869410960217735169
spelling Investigating the role of mitochondrial dysfunction in the pathogenesis of Parkinsons´s disease using patient-specific derived astrocytesFernández Carasa, IreneMalalties neurodegenerativesEnfermedades neurodegenerativasNeurodegenerative DiseasesMalaltia de ParkinsonEnfermedad de ParkinsonParkinson's diseaseCèl·lules mareCélulas madreStem cellsNeurògliaNeurogliaCitologiaCitologíaCytologyCiències Experimentals i Matemàtiques577Programa de Doctorat en BiomedicinaParkinson’s disease (PD) is an incurable, chronically progressive disorder of old age leading to premature invalidity and death. Clinically, PD is characterized by classical motor syndrome linked to a progressive loss of dopamine-containing neurons (DAn) in the substantia nigra pars compacta, and disabling non-motor symptoms related to extranigral lesions. The identification of several genes associated to familiar PD have brought considerable insight into underlying pathogenic mechanisms. However, the unknown etiology of the sporadic forms (90% of patients) and the emerging view that non-neuronal cells could be also implicated in the pathophysiology of the disease, greatly impact on the development of accurate models and on the discovery of a cure. Here, I investigate the role of astrocytes in disease pathogenesis using a human iPSC-based model of Parkinson’s disease. First, I introduce Parkinson’s disease, its pathological hallmarks and the progression of the symptoms, and discuss genetic and environmental influences. Then, I elaborate on the different mechanisms involved in PD including mitochondrial dysfunction, oxidative stress and autophagy as well as on the inflammatory phenotypes observed in the disease and recent work describing the role of inflammation in PD animal models and post-mortem brain tissue. Subsequently, I examine the association of astrocytic dysfunctions with neuronal morphological and functional abnormalities that contribute to the progression of several neurodegenerative including Parkinson’s disease and the recent data showing an astrocyte-autonomous process mediating PD-associated degeneration of dopaminergic neurons, mainly via intracellular accumulation of α-synuclein aggregates in astrocytes and subsequent propagation of such toxic aggregates to surrounding neurons. In the results section, I describe the generation and characterization of iPSC- derived astrocytes of LRRK2-PD patients (LRRK2G2019S PD), healthy individual (Ctrl) and CRISPR/Cas9 gene edited isogenic control. I show that LRRK2G2019S PD astrocytes exhibited extensive perinuclear accumulation of fragmented mitochondria and a significant increase in DRP1 phosphorylation compared to control astrocytes. Fragmented mitochondria accumulated in LRRK2G2019S PD astrocytes was due to a defective mitophagy leading to an increase in oxidative stress. I also show that oxygen consumption rate, ATP production and mitochondrial membrane potential were significantly decreased in LRRK2G2019S PD astrocytes indicating altered mitochondrial function in PD astrocytes and that LRRK2G2019S PD astrocytes exhibited lower expression levels of mitochondrial biogenesis-related genes compared to control astrocytes. Importantly, correction of G2019S mutation in the LRRK2 gene by CRISPR-Cas9 gene editing normalized mitochondria morphology, clearance and function to those of control astrocytes. Then, I describe the effects of Urolithin A, a mitophagy activator drug, that was able to rescue mitochondrial fragmentation and accumulation in LRRK2G2019S PD astrocytes by inducing mitophagy, promoting expression of mitochondrial biogenesis-related genes and reducing ROS production in those astrocytes. Finally, in the last chapter, I show that, in a co-culture system established between LRRK2G2019S PD astrocytes and healthy DA neurons, the treatment with Urolithin A, prevented neuronal cell death, suggesting a potential astrocyte- targeted therapeutic. In conclusion, our findings provide the advantage for using iPSC-based modeling for assessing the consequences of mitochondrial dysfunctions in astrocytes and dissecting the initial mechanisms that lead to neuronal cell loss in PD. The present modeling has uncovered mitophagy dysfunction as a relevant altered mechanism in PD astrocytes whose activation might represent an interesting therapeutic option for counteracting PD-related neurodegeneration.Universitat de BarcelonaConsiglio, AntonellaRío Fernández, José Antonio delUniversitat de Barcelona. Facultat de Biologia202220222021info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersion181 p.application/pdfapplication/pdfhttp://hdl.handle.net/10803/673716TDX (Tesis Doctorals en Xarxa)reponame:TDR. Tesis Doctorales en Redinstname:CBUC, CESCAInglésADVERTIMENT. Tots els drets reservats. L'accés als continguts d'aquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials d'investigació i docència en els termes establerts a l'art. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix l'autorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No s'autoritza la seva reproducció o altres formes d'explotació efectuades amb finalitats de lucre ni la seva comunicació pública des d'un lloc aliè al servei TDX. Tampoc s'autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs.info:eu-repo/semantics/openAccessoai:www.tdx.cat:10803/6737162026-06-14T12:46:07Z
score 15,300724

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