Microglial implication in Parkinson's Disease: studying functional and morphological changes occurring in LRRK2 microglia during PD pathophysiology using a stem cell derived human model

Programa de Doctorat en Biomedicina

Detalles Bibliográficos
Autor: Blasco Agell, Lucas
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:10803/688708
Acceso en línea:http://hdl.handle.net/10803/688708
Access Level:acceso abierto
Palabra clave:Micròglia
Microglia
Malaltia de Parkinson
Enfermedad de Parkinson
Parkinson's disease
Cèl·lules mare
Células madre
Stem cells
Inflamació
Inflamación
Inflammation
Ciències de la Salut
616.8
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spelling Microglial implication in Parkinson's Disease: studying functional and morphological changes occurring in LRRK2 microglia during PD pathophysiology using a stem cell derived human modelBlasco Agell, LucasMicrògliaMicrogliaMalaltia de ParkinsonEnfermedad de ParkinsonParkinson's diseaseCèl·lules mareCélulas madreStem cellsInflamacióInflamaciónInflammationCiències de la Salut616.8Programa de Doctorat en Biomedicina[eng] Parkinson’s disease (PD) is an incurable neurodegenerative disease characterized by the loss of neuromelanin (NM)-containing dopamine neurons in Substantia Nigra pars compacta (SNpc) and accumulation of insoluble cytoplasmic protein inclusions known as Lewy bodies. Microglial activation, astrocyte reactivity and lymphocyte infiltration also occur in PD. Here, we hypothesize that PD is initiated years before the emergence of motor dysfunction in response to several mechanisms some of which triggered following microglia activation that impact negatively in neuronal survival. Taking advantage of our human iPSC-based model of PD, we first generated human Microglia-like cells (hMG) from LRRK2-PD and Control iPSCs and confirmed their identity by using specific microglial markers. We then carried out functional studies with pro-inflammatory stimuli such as LPS or NM, which revealed a higher motility, cytokine release and phagocytic activity of LRRK2-PD hMG compared to control hMG. In addition, we found that extracellular NM particles induced microglial activation and increases ROS production in LRRK2-PD microglia. The use of a corrected isogenic PD hMG reverted all previous phenotypes, confirming a LRRK2-dependent activation of hMG. Upon co-culture with LRRK2-PD hMG and in the presence of NM particles, Control Dopaminergic neurons (DAn) displayed morphological signs of neurodegeneration, such as short and few neurites as well as beaded necklace-like neurites, as well as increased neuronal loss. Thus, our findings indicate a critical role for neuromelanin-activated microglia in LRRK2-PD and may serve as a valid human cellular model to test compounds that can lower risk for PD or disease progression.Universitat de BarcelonaConsiglio, AntonellaPons Espinal, MeritxellConsiglio, AntonellaUniversitat de Barcelona. Facultat de Medicina i Ciències de la Salut202320232021info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersion185 p.application/pdfhttp://hdl.handle.net/10803/688708TDX (Tesis Doctorals en Xarxa)reponame:TDR. Tesis Doctorales en Redinstname:CBUC, CESCAInglésL'accés als continguts d'aquesta tesi queda condicionat a l'acceptació de les condicions d'ús establertes per la següent llicència Creative Commons: http://creativecommons.org/licenses/by/4.0/http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:www.tdx.cat:10803/6887082026-06-14T12:46:07Z
dc.title.none.fl_str_mv Microglial implication in Parkinson's Disease: studying functional and morphological changes occurring in LRRK2 microglia during PD pathophysiology using a stem cell derived human model
title Microglial implication in Parkinson's Disease: studying functional and morphological changes occurring in LRRK2 microglia during PD pathophysiology using a stem cell derived human model
spellingShingle Microglial implication in Parkinson's Disease: studying functional and morphological changes occurring in LRRK2 microglia during PD pathophysiology using a stem cell derived human model
Blasco Agell, Lucas
Micròglia
Microglia
Malaltia de Parkinson
Enfermedad de Parkinson
Parkinson's disease
Cèl·lules mare
Células madre
Stem cells
Inflamació
Inflamación
Inflammation
Ciències de la Salut
616.8
title_short Microglial implication in Parkinson's Disease: studying functional and morphological changes occurring in LRRK2 microglia during PD pathophysiology using a stem cell derived human model
title_full Microglial implication in Parkinson's Disease: studying functional and morphological changes occurring in LRRK2 microglia during PD pathophysiology using a stem cell derived human model
title_fullStr Microglial implication in Parkinson's Disease: studying functional and morphological changes occurring in LRRK2 microglia during PD pathophysiology using a stem cell derived human model
title_full_unstemmed Microglial implication in Parkinson's Disease: studying functional and morphological changes occurring in LRRK2 microglia during PD pathophysiology using a stem cell derived human model
title_sort Microglial implication in Parkinson's Disease: studying functional and morphological changes occurring in LRRK2 microglia during PD pathophysiology using a stem cell derived human model
dc.creator.none.fl_str_mv Blasco Agell, Lucas
author Blasco Agell, Lucas
author_facet Blasco Agell, Lucas
author_role author
dc.contributor.none.fl_str_mv Consiglio, Antonella
Pons Espinal, Meritxell
Consiglio, Antonella
Universitat de Barcelona. Facultat de Medicina i Ciències de la Salut
dc.subject.none.fl_str_mv Micròglia
Microglia
Malaltia de Parkinson
Enfermedad de Parkinson
Parkinson's disease
Cèl·lules mare
Células madre
Stem cells
Inflamació
Inflamación
Inflammation
Ciències de la Salut
616.8
topic Micròglia
Microglia
Malaltia de Parkinson
Enfermedad de Parkinson
Parkinson's disease
Cèl·lules mare
Células madre
Stem cells
Inflamació
Inflamación
Inflammation
Ciències de la Salut
616.8
description Programa de Doctorat en Biomedicina
publishDate 2021
dc.date.none.fl_str_mv 2021
2023
2023
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/10803/688708
url http://hdl.handle.net/10803/688708
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 185 p.
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_ 1869411040840646656
score 15,301603

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