Naringenin and SMER28 target lysosomal reformation and rescue SPG11 and SPG15 hereditary spastic paraplegia phenotypes
SPG11 and SPG15 are two hereditary spastic paraplegia forms characterized by autophagosome accumulation, reduced free lysosomes and defects in autophagic lysosomal reformation (ALR). We demonstrated that attempts to rescue ALR and/or lysosome biogenesis are critical strategies for SPG15 phenotype an...
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Elsevier
2025-08-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661825002610 |
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| author | Chiara Vantaggiato Giulia Guarato Francesca Brivio Elena Panzeri Beatrice Speltoni Sentiljana Gumeni Genny Orso Filippo Maria Santorelli Maria Teresa Bassi |
| author_facet | Chiara Vantaggiato Giulia Guarato Francesca Brivio Elena Panzeri Beatrice Speltoni Sentiljana Gumeni Genny Orso Filippo Maria Santorelli Maria Teresa Bassi |
| author_sort | Chiara Vantaggiato |
| collection | DOAJ |
| description | SPG11 and SPG15 are two hereditary spastic paraplegia forms characterized by autophagosome accumulation, reduced free lysosomes and defects in autophagic lysosomal reformation (ALR). We demonstrated that attempts to rescue ALR and/or lysosome biogenesis are critical strategies for SPG15 phenotype and that SMER28 improved lysosomal reformation rescuing locomotor deficit in a SPG15 Drosophila model. Here we assessed the therapeutic potential of two FDA-approved compounds, tideglusib and naringenin, that target lysosomal function and regeneration, both registered for clinical use. Their effects were compared with those of SMER28 and of miglustat, the latter tested in a phase II clinical trial in SPG11 patients, in both SPG15 and SPG11 patient’s derived cells and in the corresponding Drosophila models. We demonstrated that naringenin and SMER28 restored lysosomal and autophagic parameters in SPG15 and SPG11 cells and fly models, rescued ALR and improved locomotor deficit in vivo. Both compounds induced lysosomal tubulation, downstream of mTOR, promoting lysosomal reformation. Our work indicates that lysosomal reformation is a good strategy for herditary spastic parapegia forms with impaired lysosomal function and identifies naringenin as new modulator of this process, offering further hand to planning phase II clinical trials in SPG11-SPG15 patients. |
| format | Article |
| id | doaj-art-7d39a5f9f7ff4367b540a97b415b1007 |
| institution | DOAJ |
| issn | 1096-1186 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
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| series | Pharmacological Research |
| spelling | doaj-art-7d39a5f9f7ff4367b540a97b415b10072025-08-20T03:13:42ZengElsevierPharmacological Research1096-11862025-08-0121810783610.1016/j.phrs.2025.107836Naringenin and SMER28 target lysosomal reformation and rescue SPG11 and SPG15 hereditary spastic paraplegia phenotypesChiara Vantaggiato0Giulia Guarato1Francesca Brivio2Elena Panzeri3Beatrice Speltoni4Sentiljana Gumeni5Genny Orso6Filippo Maria Santorelli7Maria Teresa Bassi8Scientific Institute IRCCS E. Medea, Laboratory of Medical Genetics, Via D. L. Monza 20, Bosisio Parini, Lecco 23842, Italy; Correspondence to: Scientific Institute, IRCCS E. Medea, Laboratory of Molecular Biology, Via D. L. Monza 20, 23842 Bosisio Parini, Lecco, Italy.Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Largo E. Meneghetti 2, Padova, ItalyScientific Institute IRCCS E. Medea, Laboratory of Medical Genetics, Via D. L. Monza 20, Bosisio Parini, Lecco 23842, Italy; Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Largo E. Meneghetti 2, Padova, ItalyScientific Institute IRCCS E. Medea, Laboratory of Medical Genetics, Via D. L. Monza 20, Bosisio Parini, Lecco 23842, ItalyDepartment of Pharmaceutical and Pharmacological Sciences, University of Padova, Largo E. Meneghetti 2, Padova, ItalyDepartment of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens, Athens, GreeceDepartment of Pharmaceutical and Pharmacological Sciences, University of Padova, Largo E. Meneghetti 2, Padova, Italy; Corresponding author.IRCCS Stella Maris Foundation, Pisa 56128, ItalyScientific Institute IRCCS E. Medea, Laboratory of Medical Genetics, Via D. L. Monza 20, Bosisio Parini, Lecco 23842, ItalySPG11 and SPG15 are two hereditary spastic paraplegia forms characterized by autophagosome accumulation, reduced free lysosomes and defects in autophagic lysosomal reformation (ALR). We demonstrated that attempts to rescue ALR and/or lysosome biogenesis are critical strategies for SPG15 phenotype and that SMER28 improved lysosomal reformation rescuing locomotor deficit in a SPG15 Drosophila model. Here we assessed the therapeutic potential of two FDA-approved compounds, tideglusib and naringenin, that target lysosomal function and regeneration, both registered for clinical use. Their effects were compared with those of SMER28 and of miglustat, the latter tested in a phase II clinical trial in SPG11 patients, in both SPG15 and SPG11 patient’s derived cells and in the corresponding Drosophila models. We demonstrated that naringenin and SMER28 restored lysosomal and autophagic parameters in SPG15 and SPG11 cells and fly models, rescued ALR and improved locomotor deficit in vivo. Both compounds induced lysosomal tubulation, downstream of mTOR, promoting lysosomal reformation. Our work indicates that lysosomal reformation is a good strategy for herditary spastic parapegia forms with impaired lysosomal function and identifies naringenin as new modulator of this process, offering further hand to planning phase II clinical trials in SPG11-SPG15 patients.http://www.sciencedirect.com/science/article/pii/S1043661825002610NaringeninTideglusibSMER28ALRLysosomesSPG15 |
| spellingShingle | Chiara Vantaggiato Giulia Guarato Francesca Brivio Elena Panzeri Beatrice Speltoni Sentiljana Gumeni Genny Orso Filippo Maria Santorelli Maria Teresa Bassi Naringenin and SMER28 target lysosomal reformation and rescue SPG11 and SPG15 hereditary spastic paraplegia phenotypes Pharmacological Research Naringenin Tideglusib SMER28 ALR Lysosomes SPG15 |
| title | Naringenin and SMER28 target lysosomal reformation and rescue SPG11 and SPG15 hereditary spastic paraplegia phenotypes |
| title_full | Naringenin and SMER28 target lysosomal reformation and rescue SPG11 and SPG15 hereditary spastic paraplegia phenotypes |
| title_fullStr | Naringenin and SMER28 target lysosomal reformation and rescue SPG11 and SPG15 hereditary spastic paraplegia phenotypes |
| title_full_unstemmed | Naringenin and SMER28 target lysosomal reformation and rescue SPG11 and SPG15 hereditary spastic paraplegia phenotypes |
| title_short | Naringenin and SMER28 target lysosomal reformation and rescue SPG11 and SPG15 hereditary spastic paraplegia phenotypes |
| title_sort | naringenin and smer28 target lysosomal reformation and rescue spg11 and spg15 hereditary spastic paraplegia phenotypes |
| topic | Naringenin Tideglusib SMER28 ALR Lysosomes SPG15 |
| url | http://www.sciencedirect.com/science/article/pii/S1043661825002610 |
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