Nanoparticles encapsulating phosphatidylinositol derivatives promote neuroprotection and functional improvement in preclinical models of ALS via a long-lasting activation of TRPML1 lysosomal channel
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease currently incurable, in which motor neuron degeneration leads to voluntary skeletal muscle atrophy. Molecularly, ALS is characterized by protein aggregation, synaptic and organellar dysfunction, and Ca2+ dyshomeostasis. O...
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Elsevier
2024-12-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661824004365 |
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| author | Valentina Tedeschi Valeria Nele Valeria Valsecchi Serenella Anzilotti Antonio Vinciguerra Laura Zucaro Maria Josè Sisalli Chiara Cassiano Nunzia De Iesu Giuseppe Pignataro Lorella Maria Teresa Canzoniero Anna Pannaccione Giuseppe De Rosa Agnese Secondo |
| author_facet | Valentina Tedeschi Valeria Nele Valeria Valsecchi Serenella Anzilotti Antonio Vinciguerra Laura Zucaro Maria Josè Sisalli Chiara Cassiano Nunzia De Iesu Giuseppe Pignataro Lorella Maria Teresa Canzoniero Anna Pannaccione Giuseppe De Rosa Agnese Secondo |
| author_sort | Valentina Tedeschi |
| collection | DOAJ |
| description | Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease currently incurable, in which motor neuron degeneration leads to voluntary skeletal muscle atrophy. Molecularly, ALS is characterized by protein aggregation, synaptic and organellar dysfunction, and Ca2+ dyshomeostasis. Of interest, autophagy dysfunction is emerging as one of the main putative targets of ALS therapy. A tune regulation of this cleansing process is affordable by a proper stimulation of TRPML1, one of the main lysosomal channels. However, TRPML1 activation by PI(3,5)P2 has low open probability to remain in an active conformation. To overcome this drawback we developed a lipid-based formulation of PI(3,5)P2 whose putative therapeutic potential has been tested in in vitro and in vivo ALS models.Pharmacodynamic properties of PI(3,5)P2 lipid-based formulations (F1 and F2) on TRPML1 activity have been characterized by means of patch-clamp electrophysiology and Fura-2AM video-imaging in motor neuronal cells. Once selected for the ability to stabilize TRPML1 activity, the most effective preparation F1 was studied in vivo to measure neuromuscular function and survival of SOD1G93A ALS mice, thereby establishing its therapeutic profile.F1, but not PI(3,5)P2 alone, stabilized the open state of the lysosomal channel TRPML1 and increased the persistence of intracellular calcium concentration ([Ca2+]i). Then, F1 was effective in delaying motor neuron loss, improving innervated endplants and muscle performance in SOD1G93A mice, extending overall lifespan by an average of 10 days. Of note F1 prevented gliosis and autophagy dysfunction in ALS mice by restoring PI(3,5)P2 level.Our novel self-assembling lipidic formulation for PI(3,5)P2 delivery exerts a neuroprotective effect in preclinical models of ALS mainly regulating dysfunctional autophagy through TRPML1 activity stabilization. |
| format | Article |
| id | doaj-art-cc4e8c75c90540188d38409887dbf77d |
| institution | OA Journals |
| issn | 1096-1186 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
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| series | Pharmacological Research |
| spelling | doaj-art-cc4e8c75c90540188d38409887dbf77d2025-08-20T02:37:03ZengElsevierPharmacological Research1096-11862024-12-0121010749110.1016/j.phrs.2024.107491Nanoparticles encapsulating phosphatidylinositol derivatives promote neuroprotection and functional improvement in preclinical models of ALS via a long-lasting activation of TRPML1 lysosomal channelValentina Tedeschi0Valeria Nele1Valeria Valsecchi2Serenella Anzilotti3Antonio Vinciguerra4Laura Zucaro5Maria Josè Sisalli6Chiara Cassiano7Nunzia De Iesu8Giuseppe Pignataro9Lorella Maria Teresa Canzoniero10Anna Pannaccione11Giuseppe De Rosa12Agnese Secondo13Division of Pharmacology, Department of Neuroscience, Reproductive and Odontostomatological Sciences, School of Medicine, University of Naples “Federico II”, Via S. Pansini 5, Naples 80131, ItalyDepartment of Pharmacy, University of Naples “Federico II”, Via D. Montesano 49, Naples 80131, ItalyDivision of Pharmacology, Department of Neuroscience, Reproductive and Odontostomatological Sciences, School of Medicine, University of Naples “Federico II”, Via S. Pansini 5, Naples 80131, ItalyDepartment of Science and Technology-DST, University of Sannio, Via Port'Arsa 11, Benevento 82100, ItalyDepartment of Biomedical Sciences and Public Health, School of Medicine, University “Politecnica Delle Marche”, Via Tronto 10/A, Ancona 60126, ItalyBiogem Scarl, Istituto di Ricerche Genetiche, Ariano Irpino, AV, Italy; Department of Translational Medical Sciences, Università degli Studi della Campania “Luigi Vanvitelli”, Naples, ItalyDepartment of Translational Medical Sciences, University of Naples “Federico II”, Via S. Pansini 5, Naples 80131, ItalyDepartment of Pharmacy, University of Naples “Federico II”, Via D. Montesano 49, Naples 80131, ItalyIRCCS SYNLAB SDN S.p.A., Naples 80143, ItalyDivision of Pharmacology, Department of Neuroscience, Reproductive and Odontostomatological Sciences, School of Medicine, University of Naples “Federico II”, Via S. Pansini 5, Naples 80131, ItalyDepartment of Science and Technology-DST, University of Sannio, Via Port'Arsa 11, Benevento 82100, ItalyDivision of Pharmacology, Department of Neuroscience, Reproductive and Odontostomatological Sciences, School of Medicine, University of Naples “Federico II”, Via S. Pansini 5, Naples 80131, ItalyDepartment of Pharmacy, University of Naples “Federico II”, Via D. Montesano 49, Naples 80131, Italy; Corresponding authors.Department of Biomedical Sciences and Public Health, School of Medicine, University “Politecnica Delle Marche”, Via Tronto 10/A, Ancona 60126, Italy; Corresponding authors.Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease currently incurable, in which motor neuron degeneration leads to voluntary skeletal muscle atrophy. Molecularly, ALS is characterized by protein aggregation, synaptic and organellar dysfunction, and Ca2+ dyshomeostasis. Of interest, autophagy dysfunction is emerging as one of the main putative targets of ALS therapy. A tune regulation of this cleansing process is affordable by a proper stimulation of TRPML1, one of the main lysosomal channels. However, TRPML1 activation by PI(3,5)P2 has low open probability to remain in an active conformation. To overcome this drawback we developed a lipid-based formulation of PI(3,5)P2 whose putative therapeutic potential has been tested in in vitro and in vivo ALS models.Pharmacodynamic properties of PI(3,5)P2 lipid-based formulations (F1 and F2) on TRPML1 activity have been characterized by means of patch-clamp electrophysiology and Fura-2AM video-imaging in motor neuronal cells. Once selected for the ability to stabilize TRPML1 activity, the most effective preparation F1 was studied in vivo to measure neuromuscular function and survival of SOD1G93A ALS mice, thereby establishing its therapeutic profile.F1, but not PI(3,5)P2 alone, stabilized the open state of the lysosomal channel TRPML1 and increased the persistence of intracellular calcium concentration ([Ca2+]i). Then, F1 was effective in delaying motor neuron loss, improving innervated endplants and muscle performance in SOD1G93A mice, extending overall lifespan by an average of 10 days. Of note F1 prevented gliosis and autophagy dysfunction in ALS mice by restoring PI(3,5)P2 level.Our novel self-assembling lipidic formulation for PI(3,5)P2 delivery exerts a neuroprotective effect in preclinical models of ALS mainly regulating dysfunctional autophagy through TRPML1 activity stabilization.http://www.sciencedirect.com/science/article/pii/S1043661824004365SANPNeuroprotectionAutophagyTRPML1PI(3,5)P2ALS |
| spellingShingle | Valentina Tedeschi Valeria Nele Valeria Valsecchi Serenella Anzilotti Antonio Vinciguerra Laura Zucaro Maria Josè Sisalli Chiara Cassiano Nunzia De Iesu Giuseppe Pignataro Lorella Maria Teresa Canzoniero Anna Pannaccione Giuseppe De Rosa Agnese Secondo Nanoparticles encapsulating phosphatidylinositol derivatives promote neuroprotection and functional improvement in preclinical models of ALS via a long-lasting activation of TRPML1 lysosomal channel Pharmacological Research SANP Neuroprotection Autophagy TRPML1 PI(3,5)P2 ALS |
| title | Nanoparticles encapsulating phosphatidylinositol derivatives promote neuroprotection and functional improvement in preclinical models of ALS via a long-lasting activation of TRPML1 lysosomal channel |
| title_full | Nanoparticles encapsulating phosphatidylinositol derivatives promote neuroprotection and functional improvement in preclinical models of ALS via a long-lasting activation of TRPML1 lysosomal channel |
| title_fullStr | Nanoparticles encapsulating phosphatidylinositol derivatives promote neuroprotection and functional improvement in preclinical models of ALS via a long-lasting activation of TRPML1 lysosomal channel |
| title_full_unstemmed | Nanoparticles encapsulating phosphatidylinositol derivatives promote neuroprotection and functional improvement in preclinical models of ALS via a long-lasting activation of TRPML1 lysosomal channel |
| title_short | Nanoparticles encapsulating phosphatidylinositol derivatives promote neuroprotection and functional improvement in preclinical models of ALS via a long-lasting activation of TRPML1 lysosomal channel |
| title_sort | nanoparticles encapsulating phosphatidylinositol derivatives promote neuroprotection and functional improvement in preclinical models of als via a long lasting activation of trpml1 lysosomal channel |
| topic | SANP Neuroprotection Autophagy TRPML1 PI(3,5)P2 ALS |
| url | http://www.sciencedirect.com/science/article/pii/S1043661824004365 |
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