Alpha-synuclein inclusions reduced by PIKfyve inhibition in Parkinson disease cell models
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-aggrega...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-10-01
|
| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996125002694 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849227024724393984 |
|---|---|
| author | Sara Lucas-Del-Pozo Giuseppe Uras Federico Fierli Veronica Lentini Sofia Koletsi Carlos Lazaro-Hernandez Kai-Yin Chau Derralynn A. Hughes Anthony H.V. Schapira |
| author_facet | Sara Lucas-Del-Pozo Giuseppe Uras Federico Fierli Veronica Lentini Sofia Koletsi Carlos Lazaro-Hernandez Kai-Yin Chau Derralynn A. Hughes Anthony H.V. Schapira |
| author_sort | Sara Lucas-Del-Pozo |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-a6faeffafa8e48eeaee39207aff3f29e |
| institution | Kabale University |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-a6faeffafa8e48eeaee39207aff3f29e2025-08-24T05:11:30ZengElsevierNeurobiology of Disease1095-953X2025-10-0121510705310.1016/j.nbd.2025.107053Alpha-synuclein inclusions reduced by PIKfyve inhibition in Parkinson disease cell modelsSara Lucas-Del-Pozo0Giuseppe Uras1Federico Fierli2Veronica Lentini3Sofia Koletsi4Carlos Lazaro-Hernandez5Kai-Yin Chau6Derralynn A. Hughes7Anthony H.V. Schapira8Department 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, USADepartment 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 07100, ItalyDepartment 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, USADepartment of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK; Department of Biomedical Science, University of Sassari, Viale San Pietro, Sassari 07100, ItalyDepartment 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, USADepartment of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK; Neurology Department, Vall d'Hebron University Hospital, Barcelona, SpainDepartment 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, USALysosomal Storage Disorders Unit, Royal Free Hospital NHS Foundation Trust and University College London, London, UKDepartment 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; Corresponding author at: UCL Queen Square Institute of Neurology, Royal Free Campus, Rowland Hill Street, Hampstead, London NW3 2PF, UK.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.http://www.sciencedirect.com/science/article/pii/S0969996125002694Parkinson's diseaseAlpha-synucleinTFEBPIKfyve |
| spellingShingle | Sara Lucas-Del-Pozo Giuseppe Uras Federico Fierli Veronica Lentini Sofia Koletsi Carlos Lazaro-Hernandez Kai-Yin Chau Derralynn A. Hughes Anthony H.V. Schapira Alpha-synuclein inclusions reduced by PIKfyve inhibition in Parkinson disease cell models Neurobiology of Disease Parkinson's disease Alpha-synuclein TFEB PIKfyve |
| title | 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_short | 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 |
| topic | Parkinson's disease Alpha-synuclein TFEB PIKfyve |
| url | http://www.sciencedirect.com/science/article/pii/S0969996125002694 |
| work_keys_str_mv | AT saralucasdelpozo alphasynucleininclusionsreducedbypikfyveinhibitioninparkinsondiseasecellmodels AT giuseppeuras alphasynucleininclusionsreducedbypikfyveinhibitioninparkinsondiseasecellmodels AT federicofierli alphasynucleininclusionsreducedbypikfyveinhibitioninparkinsondiseasecellmodels AT veronicalentini alphasynucleininclusionsreducedbypikfyveinhibitioninparkinsondiseasecellmodels AT sofiakoletsi alphasynucleininclusionsreducedbypikfyveinhibitioninparkinsondiseasecellmodels AT carloslazarohernandez alphasynucleininclusionsreducedbypikfyveinhibitioninparkinsondiseasecellmodels AT kaiyinchau alphasynucleininclusionsreducedbypikfyveinhibitioninparkinsondiseasecellmodels AT derralynnahughes alphasynucleininclusionsreducedbypikfyveinhibitioninparkinsondiseasecellmodels AT anthonyhvschapira alphasynucleininclusionsreducedbypikfyveinhibitioninparkinsondiseasecellmodels |