Alpha-synuclein inclusions reduced by PIKfyve inhibition in Parkinson disease cell models

Alpha-synuclein; PIKfyve; Parkinson's disease

Bibliographic Details
Authors: Lucas-Del-Pozo, Sara, Uras, Giuseppe, Fierli, Federico, Lentini, Veronica, Koletsi, Sofia, Lázaro Hernández, Carlos
Format: article
Status:Published version
Publication Date:2025
Country:España
Institution:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repository:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:11351/13970
Online Access:http://hdl.handle.net/11351/13970
Access Level:Open access
Keyword:Neurones dopaminèrgiques
Parkinson, Malaltia de
Inhibidors enzimàtics
DISEASES::Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Basal Ganglia Diseases::Parkinsonian Disorders::Parkinson Disease
CHEMICALS AND DRUGS::Amino Acids, Peptides, and Proteins::Proteins::Nerve Tissue Proteins::Synucleins::alpha-Synuclein
ANATOMY::Nervous System::Neurons::Dopaminergic Neurons
CHEMICALS AND DRUGS::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors
ENFERMEDADES::enfermedades del sistema nervioso::enfermedades del sistema nervioso central::enfermedades cerebrales::enfermedades de los ganglios basales::trastornos parkinsonianos::enfermedad de Parkinson
COMPUESTOS QUÍMICOS Y DROGAS::aminoácidos, péptidos y proteínas::proteínas::proteínas del tejido nervioso::sinucleínas::alfa-sinucleína
ANATOMÍA::sistema nervioso::neuronas::neuronas dopaminérgicas
COMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos
id ES_87bb35940ecccd6759fc3dd7d21a5ada
oai_identifier_str oai:recercat.cat:11351/13970
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Alpha-synuclein inclusions reduced by PIKfyve inhibition in Parkinson disease cell models
title Alpha-synuclein inclusions reduced by PIKfyve inhibition in Parkinson disease cell models
spellingShingle Alpha-synuclein inclusions reduced by PIKfyve inhibition in Parkinson disease cell models
Lucas-Del-Pozo, Sara
Neurones dopaminèrgiques
Parkinson, Malaltia de
Inhibidors enzimàtics
DISEASES::Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Basal Ganglia Diseases::Parkinsonian Disorders::Parkinson Disease
CHEMICALS AND DRUGS::Amino Acids, Peptides, and Proteins::Proteins::Nerve Tissue Proteins::Synucleins::alpha-Synuclein
ANATOMY::Nervous System::Neurons::Dopaminergic Neurons
CHEMICALS AND DRUGS::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors
ENFERMEDADES::enfermedades del sistema nervioso::enfermedades del sistema nervioso central::enfermedades cerebrales::enfermedades de los ganglios basales::trastornos parkinsonianos::enfermedad de Parkinson
COMPUESTOS QUÍMICOS Y DROGAS::aminoácidos, péptidos y proteínas::proteínas::proteínas del tejido nervioso::sinucleínas::alfa-sinucleína
ANATOMÍA::sistema nervioso::neuronas::neuronas dopaminérgicas
COMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos
title_short Alpha-synuclein inclusions reduced by PIKfyve inhibition in Parkinson disease cell models
title_full Alpha-synuclein inclusions reduced by PIKfyve inhibition in Parkinson disease cell models
title_fullStr Alpha-synuclein inclusions reduced by PIKfyve inhibition in Parkinson disease cell models
title_full_unstemmed Alpha-synuclein inclusions reduced by PIKfyve inhibition in Parkinson disease cell models
title_sort Alpha-synuclein inclusions reduced by PIKfyve inhibition in Parkinson disease cell models
dc.creator.none.fl_str_mv Lucas-Del-Pozo, Sara
Uras, Giuseppe
Fierli, Federico
Lentini, Veronica
Koletsi, Sofia
Lázaro Hernández, Carlos
author Lucas-Del-Pozo, Sara
author_facet Lucas-Del-Pozo, Sara
Uras, Giuseppe
Fierli, Federico
Lentini, Veronica
Koletsi, Sofia
Lázaro Hernández, Carlos
author_role author
author2 Uras, Giuseppe
Fierli, Federico
Lentini, Veronica
Koletsi, Sofia
Lázaro Hernández, Carlos
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Institut Català de la Salut
[Lucas-Del-Pozo S, Fierli F, Koletsi S] Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK. Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA. [Uras G] Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK. Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA. Department of Biomedical Science, University of Sassari, Viale San Pietro, Sassari, Italy. [Lentini V] Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK. Department of Biomedical Science, University of Sassari, Viale San Pietro, Sassari, Italy. [Lazaro-Hernandez C] Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK. Servei de Neurologia, Vall d'Hebron Hospital Universitari, Barcelona, Spain
Vall d'Hebron Barcelona Hospital Campus
dc.subject.none.fl_str_mv Neurones dopaminèrgiques
Parkinson, Malaltia de
Inhibidors enzimàtics
DISEASES::Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Basal Ganglia Diseases::Parkinsonian Disorders::Parkinson Disease
CHEMICALS AND DRUGS::Amino Acids, Peptides, and Proteins::Proteins::Nerve Tissue Proteins::Synucleins::alpha-Synuclein
ANATOMY::Nervous System::Neurons::Dopaminergic Neurons
CHEMICALS AND DRUGS::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors
ENFERMEDADES::enfermedades del sistema nervioso::enfermedades del sistema nervioso central::enfermedades cerebrales::enfermedades de los ganglios basales::trastornos parkinsonianos::enfermedad de Parkinson
COMPUESTOS QUÍMICOS Y DROGAS::aminoácidos, péptidos y proteínas::proteínas::proteínas del tejido nervioso::sinucleínas::alfa-sinucleína
ANATOMÍA::sistema nervioso::neuronas::neuronas dopaminérgicas
COMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos
topic Neurones dopaminèrgiques
Parkinson, Malaltia de
Inhibidors enzimàtics
DISEASES::Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Basal Ganglia Diseases::Parkinsonian Disorders::Parkinson Disease
CHEMICALS AND DRUGS::Amino Acids, Peptides, and Proteins::Proteins::Nerve Tissue Proteins::Synucleins::alpha-Synuclein
ANATOMY::Nervous System::Neurons::Dopaminergic Neurons
CHEMICALS AND DRUGS::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors
ENFERMEDADES::enfermedades del sistema nervioso::enfermedades del sistema nervioso central::enfermedades cerebrales::enfermedades de los ganglios basales::trastornos parkinsonianos::enfermedad de Parkinson
COMPUESTOS QUÍMICOS Y DROGAS::aminoácidos, péptidos y proteínas::proteínas::proteínas del tejido nervioso::sinucleínas::alfa-sinucleína
ANATOMÍA::sistema nervioso::neuronas::neuronas dopaminérgicas
COMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos
description Alpha-synuclein; PIKfyve; Parkinson's disease
publishDate 2025
dc.date.none.fl_str_mv 2025
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11351/13970
http://hdl.handle.net/11351/13970
url http://hdl.handle.net/11351/13970
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Neurobiology of Disease;215
https://doi.org/10.1016/j.nbd.2025.107053
dc.rights.none.fl_str_mv Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv Scientia
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869412483230334976
spelling Alpha-synuclein inclusions reduced by PIKfyve inhibition in Parkinson disease cell modelsLucas-Del-Pozo, SaraUras, GiuseppeFierli, FedericoLentini, VeronicaKoletsi, SofiaLázaro Hernández, CarlosNeurones dopaminèrgiquesParkinson, Malaltia deInhibidors enzimàticsDISEASES::Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Basal Ganglia Diseases::Parkinsonian Disorders::Parkinson DiseaseCHEMICALS AND DRUGS::Amino Acids, Peptides, and Proteins::Proteins::Nerve Tissue Proteins::Synucleins::alpha-SynucleinANATOMY::Nervous System::Neurons::Dopaminergic NeuronsCHEMICALS AND DRUGS::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme InhibitorsENFERMEDADES::enfermedades del sistema nervioso::enfermedades del sistema nervioso central::enfermedades cerebrales::enfermedades de los ganglios basales::trastornos parkinsonianos::enfermedad de ParkinsonCOMPUESTOS QUÍMICOS Y DROGAS::aminoácidos, péptidos y proteínas::proteínas::proteínas del tejido nervioso::sinucleínas::alfa-sinucleínaANATOMÍA::sistema nervioso::neuronas::neuronas dopaminérgicasCOMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticosAlpha-synuclein; PIKfyve; Parkinson's diseaseAlfa-sinucleína; PIKfyve; Enfermedad de ParkinsonAlfa-sinucleïna; PIKfyve; Malaltia de ParkinsonObjective Parkinson's disease (PD) pathophysiology is associated with a progressive loss of dopaminergic neurons in the substantia nigra and accumulation of insoluble inclusions of misfolded alpha-synuclein. In this study, we used a neuroblastoma-derived cell model overexpressing a pro-aggregation form of alpha-synuclein and human-derived induced-pluripotent stem cells (iPSCs) to investigate the efficacy of PIKfyve-mediated lysosomal biogenesis to reduce alpha-synuclein inclusions. Methods We used high-content imaging and enzymatic assays to follow the progression of lysosomal biogenesis, lysosomal catabolism and alpha-synuclein accumulation. The cell models used recapitulated important elements of the biochemical phenotype observed in PD dopaminergic neurons, including alpha-synuclein inclusions and impaired glucocerebrosidase. Results PIKfyve inhibition by YM201636 resulted in a lysosomal-dependant reduction of alpha-synuclein inclusions as early as 24 h post-treatment. YM201636 induced an increase in nuclear translocation of TFEB, and an increase in lysosomal markers LAMP1 and HEXA. PIKfyve-inhibition was also tested in neuronal-differentiated neuroblastoma-derived cells and iPSCs-derived dopaminergic neurons. In these cells, YM201636 substantially reduced alpha-synuclein inclusions and increased TFEB nuclear localisation. Conclusion These findings suggest that PIKfyve signalling pathways could represent a therapeutic target to reduce alpha-synuclein in PD.This research was funded by Aligning Science Across Parkinson's [Grant number: ASAP000420] through the Michael J. Fox Foundation for Parkinson's Research. For the purpose of open access, the author has applied a CC BY 4.0 public copyright license to all Author Accepted Manuscripts arising from this submission.ElsevierInstitut Català de la Salut[Lucas-Del-Pozo S, Fierli F, Koletsi S] Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK. Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA. [Uras G] Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK. Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA. Department of Biomedical Science, University of Sassari, Viale San Pietro, Sassari, Italy. [Lentini V] Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK. Department of Biomedical Science, University of Sassari, Viale San Pietro, Sassari, Italy. [Lazaro-Hernandez C] Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK. Servei de Neurologia, Vall d'Hebron Hospital Universitari, Barcelona, SpainVall d'Hebron Barcelona Hospital Campus202520252025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/11351/13970http://hdl.handle.net/11351/13970Scientiareponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésNeurobiology of Disease;215https://doi.org/10.1016/j.nbd.2025.107053Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:11351/139702026-05-29T05:05:01Z
score 15,812429

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