Targeting PI3K/Akt/mTOR signaling in rodent models of PMP22 gene-dosage diseases
Abstract Haplo-insufficiency of the gene encoding the myelin protein PMP22 leads to focal myelin overgrowth in the peripheral nervous system and hereditary neuropathy with liability to pressure palsies (HNPP). Conversely, duplication of PMP22 causes Charcot-Marie-Tooth disease type 1A (CMT1A), chara...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2024-02-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s44321-023-00019-5 |
| _version_ | 1797259080517025792 |
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| author | Doris Krauter Daniela Stausberg Timon J Hartmann Stefan Volkmann Theresa Kungl David A Rasche Gesine Saher Robert Fledrich Ruth M Stassart Klaus-Armin Nave Sandra Goebbels David Ewers Michael W Sereda |
| author_facet | Doris Krauter Daniela Stausberg Timon J Hartmann Stefan Volkmann Theresa Kungl David A Rasche Gesine Saher Robert Fledrich Ruth M Stassart Klaus-Armin Nave Sandra Goebbels David Ewers Michael W Sereda |
| author_sort | Doris Krauter |
| collection | DOAJ |
| description | Abstract Haplo-insufficiency of the gene encoding the myelin protein PMP22 leads to focal myelin overgrowth in the peripheral nervous system and hereditary neuropathy with liability to pressure palsies (HNPP). Conversely, duplication of PMP22 causes Charcot-Marie-Tooth disease type 1A (CMT1A), characterized by hypomyelination of medium to large caliber axons. The molecular mechanisms of abnormal myelin growth regulation by PMP22 have remained obscure. Here, we show in rodent models of HNPP and CMT1A that the PI3K/Akt/mTOR-pathway inhibiting phosphatase PTEN is correlated in abundance with PMP22 in peripheral nerves, without evidence for direct protein interactions. Indeed, treating DRG neuron/Schwann cell co-cultures from HNPP mice with PI3K/Akt/mTOR pathway inhibitors reduced focal hypermyelination. When we treated HNPP mice in vivo with the mTOR inhibitor Rapamycin, motor functions were improved, compound muscle amplitudes were increased and pathological tomacula in sciatic nerves were reduced. In contrast, we found Schwann cell dedifferentiation in CMT1A uncoupled from PI3K/Akt/mTOR, leaving partial PTEN ablation insufficient for disease amelioration. For HNPP, the development of PI3K/Akt/mTOR pathway inhibitors may be considered as the first treatment option for pressure palsies. |
| first_indexed | 2024-04-24T23:03:44Z |
| format | Article |
| id | doaj.art-7fd4960236094ab48972800c5f7528ba |
| institution | Directory Open Access Journal |
| issn | 1757-4684 |
| language | English |
| last_indexed | 2024-04-24T23:03:44Z |
| publishDate | 2024-02-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-7fd4960236094ab48972800c5f7528ba2024-03-17T12:34:37ZengSpringer NatureEMBO Molecular Medicine1757-46842024-02-0116361664010.1038/s44321-023-00019-5Targeting PI3K/Akt/mTOR signaling in rodent models of PMP22 gene-dosage diseasesDoris Krauter0Daniela Stausberg1Timon J Hartmann2Stefan Volkmann3Theresa Kungl4David A Rasche5Gesine Saher6Robert Fledrich7Ruth M Stassart8Klaus-Armin Nave9Sandra Goebbels10David Ewers11Michael W Sereda12Research Group “Translational Neurogenetics”, Max Planck Institute for Multidisciplinary SciencesResearch Group “Translational Neurogenetics”, Max Planck Institute for Multidisciplinary SciencesResearch Group “Translational Neurogenetics”, Max Planck Institute for Multidisciplinary SciencesDepartment of Neurogenetics, Max Planck Institute for Multidisciplinary SciencesInstitute of Anatomy, University of LeipzigResearch Group “Translational Neurogenetics”, Max Planck Institute for Multidisciplinary SciencesDepartment of Neurogenetics, Max Planck Institute for Multidisciplinary SciencesInstitute of Anatomy, University of LeipzigInstitute of Neuropathology, University of LeipzigDepartment of Neurogenetics, Max Planck Institute for Multidisciplinary SciencesDepartment of Neurogenetics, Max Planck Institute for Multidisciplinary SciencesResearch Group “Translational Neurogenetics”, Max Planck Institute for Multidisciplinary SciencesResearch Group “Translational Neurogenetics”, Max Planck Institute for Multidisciplinary SciencesAbstract Haplo-insufficiency of the gene encoding the myelin protein PMP22 leads to focal myelin overgrowth in the peripheral nervous system and hereditary neuropathy with liability to pressure palsies (HNPP). Conversely, duplication of PMP22 causes Charcot-Marie-Tooth disease type 1A (CMT1A), characterized by hypomyelination of medium to large caliber axons. The molecular mechanisms of abnormal myelin growth regulation by PMP22 have remained obscure. Here, we show in rodent models of HNPP and CMT1A that the PI3K/Akt/mTOR-pathway inhibiting phosphatase PTEN is correlated in abundance with PMP22 in peripheral nerves, without evidence for direct protein interactions. Indeed, treating DRG neuron/Schwann cell co-cultures from HNPP mice with PI3K/Akt/mTOR pathway inhibitors reduced focal hypermyelination. When we treated HNPP mice in vivo with the mTOR inhibitor Rapamycin, motor functions were improved, compound muscle amplitudes were increased and pathological tomacula in sciatic nerves were reduced. In contrast, we found Schwann cell dedifferentiation in CMT1A uncoupled from PI3K/Akt/mTOR, leaving partial PTEN ablation insufficient for disease amelioration. For HNPP, the development of PI3K/Akt/mTOR pathway inhibitors may be considered as the first treatment option for pressure palsies.https://doi.org/10.1038/s44321-023-00019-5Charcot–Marie–Tooth NeuropathiesPeripheral Myelin Protein of 22 kDaMyelinSchwann CellPI3K/Akt/mTOR Signaling |
| spellingShingle | Doris Krauter Daniela Stausberg Timon J Hartmann Stefan Volkmann Theresa Kungl David A Rasche Gesine Saher Robert Fledrich Ruth M Stassart Klaus-Armin Nave Sandra Goebbels David Ewers Michael W Sereda Targeting PI3K/Akt/mTOR signaling in rodent models of PMP22 gene-dosage diseases EMBO Molecular Medicine Charcot–Marie–Tooth Neuropathies Peripheral Myelin Protein of 22 kDa Myelin Schwann Cell PI3K/Akt/mTOR Signaling |
| title | Targeting PI3K/Akt/mTOR signaling in rodent models of PMP22 gene-dosage diseases |
| title_full | Targeting PI3K/Akt/mTOR signaling in rodent models of PMP22 gene-dosage diseases |
| title_fullStr | Targeting PI3K/Akt/mTOR signaling in rodent models of PMP22 gene-dosage diseases |
| title_full_unstemmed | Targeting PI3K/Akt/mTOR signaling in rodent models of PMP22 gene-dosage diseases |
| title_short | Targeting PI3K/Akt/mTOR signaling in rodent models of PMP22 gene-dosage diseases |
| title_sort | targeting pi3k akt mtor signaling in rodent models of pmp22 gene dosage diseases |
| topic | Charcot–Marie–Tooth Neuropathies Peripheral Myelin Protein of 22 kDa Myelin Schwann Cell PI3K/Akt/mTOR Signaling |
| url | https://doi.org/10.1038/s44321-023-00019-5 |
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