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

[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, astro...

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Detalhes bibliográficos
Autor: Blasco Agell, Lucas
Tipo de documento: tese
Estado:Versão publicada
Data de publicação:2021
País:España
Recursos:Universidad de Barcelona
Repositório:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/200867
Acesso em linha:https://hdl.handle.net/2445/200867
http://hdl.handle.net/10803/688708
Access Level:Acceso aberto
Palavra-chave:Micròglia
Malaltia de Parkinson
Cèl·lules mare
Inflamació
Microglia
Parkinson's disease
Stem cells
Inflammation
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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, LucasMicrògliaMalaltia de ParkinsonCèl·lules mareInflamacióMicrogliaParkinson's diseaseStem cellsInflammation[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, MeritxellUniversitat de Barcelona. Facultat de Medicina i Ciències de la Salut2021info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/200867http://hdl.handle.net/10803/688708Tesis Doctorals - Facultat - Medicina i Ciències de la Salutreponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaIngléscc by (c) Blasco Agell, Lucas, 2023http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2008672026-05-27T06:46:51Z
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
Malaltia de Parkinson
Cèl·lules mare
Inflamació
Microglia
Parkinson's disease
Stem cells
Inflammation
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
Universitat de Barcelona. Facultat de Medicina i Ciències de la Salut
dc.subject.none.fl_str_mv Micròglia
Malaltia de Parkinson
Cèl·lules mare
Inflamació
Microglia
Parkinson's disease
Stem cells
Inflammation
topic Micròglia
Malaltia de Parkinson
Cèl·lules mare
Inflamació
Microglia
Parkinson's disease
Stem cells
Inflammation
description [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.
publishDate 2021
dc.date.none.fl_str_mv 2021
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 https://hdl.handle.net/2445/200867
http://hdl.handle.net/10803/688708
url https://hdl.handle.net/2445/200867
http://hdl.handle.net/10803/688708
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv cc by (c) Blasco Agell, Lucas, 2023
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Blasco Agell, Lucas, 2023
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 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 Tesis Doctorals - Facultat - Medicina i Ciències de la Salut
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,301603

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