Schwann Cell‐Specific Ablation of Beclin 1 Impairs Myelination and Leads to Motor and Sensory Neuropathy in Mice
Abstract The core component of the class III phosphatidylinositol 3‐kinase complex, Beclin 1, takes part in different protein networks, thus switching its role from inducing autophagy to regulating autophagosomal maturation and endosomal trafficking. While assessed in neurons, astrocytes, and microg...
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Wiley
2025-02-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202308965 |
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| author | Lisa Gambarotto Loris Russo Silvia Bresolin Luca Persano Rachele D'Amore Giulia Ronchi Federica Zen Luisa Muratori Alice Cani Samuele Negro Aram Megighian Sonia Calabrò Paola Braghetta Dario Bizzotto Matilde Cescon |
| author_facet | Lisa Gambarotto Loris Russo Silvia Bresolin Luca Persano Rachele D'Amore Giulia Ronchi Federica Zen Luisa Muratori Alice Cani Samuele Negro Aram Megighian Sonia Calabrò Paola Braghetta Dario Bizzotto Matilde Cescon |
| author_sort | Lisa Gambarotto |
| collection | DOAJ |
| description | Abstract The core component of the class III phosphatidylinositol 3‐kinase complex, Beclin 1, takes part in different protein networks, thus switching its role from inducing autophagy to regulating autophagosomal maturation and endosomal trafficking. While assessed in neurons, astrocytes, and microglia, its role is far less investigated in myelinating glia, including Schwann cells (SCs), responsible for peripheral nerve myelination. Remarkably, the dysregulation in endosomal trafficking is emerging as a pathophysiological mechanism underlying peripheral neuropathies, such as demyelinating Charcot‐Marie‐Tooth (CMT) diseases. By knocking out Beclin 1 in SCs here a novel mouse model (Becn1 cKO) is generated, developing a severe and progressive neuropathy, accompanied by involuntary tremors, body weight loss, and premature death. Ultrastructural analysis revealed abated myelination and SCs displaying enlarged cytoplasm with progressive accumulation of intracellular vesicles. Transcriptomic and histological analysis from sciatic nerves of 10‐day and 2‐month‐old mice revealed pro‐mitotic gene deregulation and increased SCs proliferation at both stages with axonal loss and increased immune infiltration in adults, well reflecting the progressive motor and sensory functional impairment that characterizes Becn1 cKO mice, compared to controls. The study establishes a further step in understanding key mechanisms in SC development and points to Beclin 1 and its regulated pathways as targets for demyelinating CMT forms. |
| format | Article |
| id | doaj-art-4b8485e818a341ebae497b19083edd53 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
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| series | Advanced Science |
| spelling | doaj-art-4b8485e818a341ebae497b19083edd532025-02-04T13:14:54ZengWileyAdvanced Science2198-38442025-02-01125n/an/a10.1002/advs.202308965Schwann Cell‐Specific Ablation of Beclin 1 Impairs Myelination and Leads to Motor and Sensory Neuropathy in MiceLisa Gambarotto0Loris Russo1Silvia Bresolin2Luca Persano3Rachele D'Amore4Giulia Ronchi5Federica Zen6Luisa Muratori7Alice Cani8Samuele Negro9Aram Megighian10Sonia Calabrò11Paola Braghetta12Dario Bizzotto13Matilde Cescon14Department of Molecular Medicine University of Padova Via U. Bassi 58/B Padova 35131 ItalyDepartment of Molecular Medicine University of Padova Via U. Bassi 58/B Padova 35131 ItalyDepartment of Women and Children's Health University of Padova via Giustiniani 3 Padova 35127 ItalyDepartment of Women and Children's Health University of Padova via Giustiniani 3 Padova 35127 ItalyDepartment of Molecular Medicine University of Padova Via U. Bassi 58/B Padova 35131 ItalyDepartment of Clinical and Biological Sciences & Neuroscience Institute Cavalieri Ottolenghi (NICO) University of Torino Regione Gonzole 10, Orbassano Torino 10043 ItalyDepartment of Clinical and Biological Sciences & Neuroscience Institute Cavalieri Ottolenghi (NICO) University of Torino Regione Gonzole 10, Orbassano Torino 10043 ItalyDepartment of Clinical and Biological Sciences & Neuroscience Institute Cavalieri Ottolenghi (NICO) University of Torino Regione Gonzole 10, Orbassano Torino 10043 ItalyDepartment of Women and Children's Health University of Padova via Giustiniani 3 Padova 35127 ItalyU.O.C. Clinica Neurologica Azienda Ospedale‐Università Padova Via Giustiniani 5 Padova 35128 ItalyDepartment of Biomedical Sciences University of Padova Via U. Bassi 58/B Padova 35131 ItalyDepartment of Molecular Medicine University of Padova Via U. Bassi 58/B Padova 35131 ItalyDepartment of Molecular Medicine University of Padova Via U. Bassi 58/B Padova 35131 ItalyDepartment of Molecular Medicine University of Padova Via U. Bassi 58/B Padova 35131 ItalyDepartment of Molecular Medicine University of Padova Via U. Bassi 58/B Padova 35131 ItalyAbstract The core component of the class III phosphatidylinositol 3‐kinase complex, Beclin 1, takes part in different protein networks, thus switching its role from inducing autophagy to regulating autophagosomal maturation and endosomal trafficking. While assessed in neurons, astrocytes, and microglia, its role is far less investigated in myelinating glia, including Schwann cells (SCs), responsible for peripheral nerve myelination. Remarkably, the dysregulation in endosomal trafficking is emerging as a pathophysiological mechanism underlying peripheral neuropathies, such as demyelinating Charcot‐Marie‐Tooth (CMT) diseases. By knocking out Beclin 1 in SCs here a novel mouse model (Becn1 cKO) is generated, developing a severe and progressive neuropathy, accompanied by involuntary tremors, body weight loss, and premature death. Ultrastructural analysis revealed abated myelination and SCs displaying enlarged cytoplasm with progressive accumulation of intracellular vesicles. Transcriptomic and histological analysis from sciatic nerves of 10‐day and 2‐month‐old mice revealed pro‐mitotic gene deregulation and increased SCs proliferation at both stages with axonal loss and increased immune infiltration in adults, well reflecting the progressive motor and sensory functional impairment that characterizes Becn1 cKO mice, compared to controls. The study establishes a further step in understanding key mechanisms in SC development and points to Beclin 1 and its regulated pathways as targets for demyelinating CMT forms.https://doi.org/10.1002/advs.202308965autophagyBeclin 1motor functionmyelinationneuropathySchwann cells |
| spellingShingle | Lisa Gambarotto Loris Russo Silvia Bresolin Luca Persano Rachele D'Amore Giulia Ronchi Federica Zen Luisa Muratori Alice Cani Samuele Negro Aram Megighian Sonia Calabrò Paola Braghetta Dario Bizzotto Matilde Cescon Schwann Cell‐Specific Ablation of Beclin 1 Impairs Myelination and Leads to Motor and Sensory Neuropathy in Mice Advanced Science autophagy Beclin 1 motor function myelination neuropathy Schwann cells |
| title | Schwann Cell‐Specific Ablation of Beclin 1 Impairs Myelination and Leads to Motor and Sensory Neuropathy in Mice |
| title_full | Schwann Cell‐Specific Ablation of Beclin 1 Impairs Myelination and Leads to Motor and Sensory Neuropathy in Mice |
| title_fullStr | Schwann Cell‐Specific Ablation of Beclin 1 Impairs Myelination and Leads to Motor and Sensory Neuropathy in Mice |
| title_full_unstemmed | Schwann Cell‐Specific Ablation of Beclin 1 Impairs Myelination and Leads to Motor and Sensory Neuropathy in Mice |
| title_short | Schwann Cell‐Specific Ablation of Beclin 1 Impairs Myelination and Leads to Motor and Sensory Neuropathy in Mice |
| title_sort | schwann cell specific ablation of beclin 1 impairs myelination and leads to motor and sensory neuropathy in mice |
| topic | autophagy Beclin 1 motor function myelination neuropathy Schwann cells |
| url | https://doi.org/10.1002/advs.202308965 |
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