dc.contributor
Institut Català de la Salut
dc.contributor
[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
dc.contributor
Vall d'Hebron Barcelona Hospital Campus
dc.contributor.author
Lucas-Del-Pozo, Sara
dc.contributor.author
Uras, Giuseppe
dc.contributor.author
Fierli, Federico
dc.contributor.author
Lentini, Veronica
dc.contributor.author
Koletsi, Sofia
dc.contributor.author
Lázaro Hernández, Carlos
dc.date.accessioned
2025-10-31T04:54:21Z
dc.date.available
2025-10-31T04:54:21Z
dc.date.issued
2025-10-30T08:42:59Z
dc.date.issued
2025-10-30T08:42:59Z
dc.date.issued
2025-10-15
dc.identifier
Lucas-Del-Pozo S, Uras G, Fierli F, Lentini V, Koletsi S, Lazaro-Hernandez C, et al. Alpha-synuclein inclusions reduced by PIKfyve inhibition in Parkinson disease cell models. Neurobiol Dis. 2025 Oct 15;215:107053.
dc.identifier
http://hdl.handle.net/11351/13970
dc.identifier
10.1016/j.nbd.2025.107053
dc.identifier
001567670500004
dc.identifier.uri
http://hdl.handle.net/11351/13970
dc.description.abstract
Alpha-synuclein; PIKfyve; Parkinson's disease
dc.description.abstract
Alfa-sinucleína; PIKfyve; Enfermedad de Parkinson
dc.description.abstract
Alfa-sinucleïna; PIKfyve; Malaltia de Parkinson
dc.description.abstract
Objective
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.
dc.description.abstract
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.
dc.format
application/pdf
dc.relation
Neurobiology of Disease;215
dc.relation
https://doi.org/10.1016/j.nbd.2025.107053
dc.rights
Attribution 4.0 International
dc.rights
http://creativecommons.org/licenses/by/4.0/
dc.rights
info:eu-repo/semantics/openAccess
dc.subject
Neurones dopaminèrgiques
dc.subject
Parkinson, Malaltia de
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Inhibidors enzimàtics
dc.subject
DISEASES::Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Basal Ganglia Diseases::Parkinsonian Disorders::Parkinson Disease
dc.subject
CHEMICALS AND DRUGS::Amino Acids, Peptides, and Proteins::Proteins::Nerve Tissue Proteins::Synucleins::alpha-Synuclein
dc.subject
ANATOMY::Nervous System::Neurons::Dopaminergic Neurons
dc.subject
CHEMICALS AND DRUGS::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors
dc.subject
ENFERMEDADES::enfermedades del sistema nervioso::enfermedades del sistema nervioso central::enfermedades cerebrales::enfermedades de los ganglios basales::trastornos parkinsonianos::enfermedad de Parkinson
dc.subject
COMPUESTOS QUÍMICOS Y DROGAS::aminoácidos, péptidos y proteínas::proteínas::proteínas del tejido nervioso::sinucleínas::alfa-sinucleína
dc.subject
ANATOMÍA::sistema nervioso::neuronas::neuronas dopaminérgicas
dc.subject
COMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos
dc.title
Alpha-synuclein inclusions reduced by PIKfyve inhibition in Parkinson disease cell models
dc.type
info:eu-repo/semantics/article
dc.type
info:eu-repo/semantics/publishedVersion
