Galc  ablation in Schwann cells produces a demyelinating peripheral neuropathy characterized by psychosine formation but lacking globoid cells

AbstractIn peripheral nerves, Schwann cells form myelin and provide trophic support to axons. We previously showed that the mitochondrial protein prohibitin 2 can localize to the axon-Schwann-cell interface and is required for developmental myelination. Whether the homologous protein prohibitin 1 has a similar role, and whether prohibitins also play important roles in Schwann cell mitochondria is unknown. Here, we show that deletion of prohibitin 1 in Schwann cells minimally perturbs development, but later triggers a severe demyelinating peripheral neuropathy. Moreover, mitochondria are heavily affected by ablation of prohibitin 1 and demyelination occurs preferentially in cells with apparent mitochondrial loss. Furthermore, in response to mitochondrial damage, Schwann cells trigger the integrated stress response, but, contrary to what was previously suggested, this response is not detrimental in this context. These results identify a role for prohibitin 1 in myelin integrity and advance our understanding about the Schwann cell response to mitochondrial damage.

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Prohibitin 1 is essential to preserve mitochondria and myelin integrity in Schwann cells.

10.21203/rs.3.rs-54990/v1 ◽

2020 ◽

Author(s):

Gustavo Della-Flora Nunes ◽

Emma Wilson ◽

Leandro Marziali ◽

Edward Hurley ◽

Nicholas Silvestri ◽

...

Keyword(s):

Nervous System ◽

Peripheral Neuropathy ◽

Schwann Cells ◽

Mitochondrial Protein ◽

Mitochondrial Damage ◽

System Function ◽

Homologous Protein ◽

Nervous System Function ◽

Demyelinating Peripheral Neuropathy ◽

Prohibitin 1

Abstract Myelin is required for nervous system function. In the peripheral nervous system, Schwann cells (SCs) form myelin and trophically support the axons they ensheath. We previously showed that the mitochondrial protein prohibitin 2 (PHB2) can localize to the axon-SC interface and is required for developmental myelination. Whether the homologous protein PHB1 has a similar role, and whether prohibitins also play important roles in SC mitochondria is unknown. Here we show that deletion of Phb1 in SCs only minimally perturbs development, but later triggers a severe demyelinating peripheral neuropathy. Moreover, mitochondria are heavily affected by ablation of Phb1 and demyelination occurs preferentially in cells with apparent mitochondrial loss. Furthermore, in response to mitochondrial damage, SCs trigger the integrated stress response (ISR), but, contrary to what was previously suggested, the ISR is not detrimental and may be beneficial in this context. These results identify a new role for PHB1 in myelin integrity and advance our understanding of how SCs respond to mitochondrial damage.

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Intrathecal gene therapy rescues a model of demyelinating peripheral neuropathy

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1522202113 ◽

2016 ◽

Vol 113 (17) ◽

pp. E2421-E2429 ◽

Cited By ~ 34

Author(s):

Alexia Kagiava ◽

Irene Sargiannidou ◽

George Theophilidis ◽

Christos Karaiskos ◽

Jan Richter ◽

...

Keyword(s):

Gene Therapy ◽

Peripheral Neuropathy ◽

Schwann Cells ◽

Peripheral Nerves ◽

Lentiviral Vector ◽

Intrathecal Injection ◽

Specific Expression ◽

Inherited Neuropathy ◽

Spinal Roots ◽

Demyelinating Peripheral Neuropathy

Inherited demyelinating peripheral neuropathies are progressive incurable diseases without effective treatment. To develop a gene therapy approach targeting myelinating Schwann cells that can be translatable, we delivered a lentiviral vector using a single lumbar intrathecal injection and a myelin-specific promoter. The human gene of interest, GJB1, which is mutated in X-linked Charcot–Marie–Tooth Disease (CMT1X), was delivered intrathecally into adult Gjb1-null mice, a genetically authentic model of CMT1X that develops a demyelinating peripheral neuropathy. We obtained widespread, stable, and cell-specific expression of connexin32 in up to 50% of Schwann cells in multiple lumbar spinal roots and peripheral nerves. Behavioral and electrophysiological analysis revealed significantly improved motor performance, quadriceps muscle contractility, and sciatic nerve conduction velocities. Furthermore, treated mice exhibited reduced numbers of demyelinated and remyelinated fibers and fewer inflammatory cells in lumbar motor roots, as well as in the femoral motor and sciatic nerves. This study demonstrates that a single intrathecal lentiviral gene delivery can lead to Schwann cell-specific expression in spinal roots extending to multiple peripheral nerves. This clinically relevant approach improves the phenotype of an inherited neuropathy mouse model and provides proof of principle for treating inherited demyelinating neuropathies.

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mTORC1 and JUN are activated after deletion of Prohibitin 1 in Schwann cells and may link mitochondrial dysfunction to demyelination

10.1101/2020.11.25.398032 ◽

2020 ◽

Author(s):

Gustavo Della-Flora Nunes ◽

Emma R. Wilson ◽

Edward Hurley ◽

Bin He ◽

Bert W. O’Malley ◽

...

Keyword(s):

Nervous System ◽

Peripheral Neuropathy ◽

Schwann Cell ◽

Mitochondrial Dysfunction ◽

Schwann Cells ◽

Critical Role ◽

Mitochondrial Protein ◽

Important Regulator ◽

Demyelinating Peripheral Neuropathy ◽

Prohibitin 1

AbstractSchwann cell (SC) mitochondria are quickly emerging as an important regulator of myelin maintenance in the peripheral nervous system (PNS). However, the mechanisms underlying demyelination in the context of mitochondrial dysfunction in the PNS are incompletely understood. We recently showed that conditional ablation of the mitochondrial protein Prohibitin 1 (Phb1) in SCs causes a severe and fast progressing demyelinating peripheral neuropathy, but the mechanism that causes failure of myelin maintenance remained unknown. Here, we report that mTORC1 and JUN are continuously activated in the absence of Phb1, likely due to mitochondrial damage. Moreover, we demonstrate that these pathways are involved in the demyelination process, and that inhibition of mTORC1 using rapamycin partially rescues the demyelinating pathology. Therefore, we propose that mTORC1 and JUN may play a critical role as executioners of demyelination in the context of perturbations to SC mitochondria.

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Activation of mTORC1 and c-Jun by Prohibitin1 loss in Schwann cells may link mitochondrial dysfunction to demyelination

eLife ◽

10.7554/elife.66278 ◽

2021 ◽

Vol 10 ◽

Author(s):

Gustavo Della Flora Nunes ◽

Emma R Wilson ◽

Edward Hurley ◽

Bin He ◽

Bert W O'Malley ◽

...

Keyword(s):

Nervous System ◽

Peripheral Neuropathy ◽

Schwann Cell ◽

Mitochondrial Dysfunction ◽

Schwann Cells ◽

Critical Role ◽

Mitochondrial Protein ◽

Important Regulator ◽

Demyelinating Peripheral Neuropathy ◽

Prohibitin 1

Schwann cell (SC) mitochondria are quickly emerging as an important regulator of myelin maintenance in the peripheral nervous system (PNS). However, the mechanisms underlying demyelination in the context of mitochondrial dysfunction in the PNS are incompletely understood. We recently showed that conditional ablation of the mitochondrial protein Prohibitin 1 (PHB1) in SCs causes a severe and fast progressing demyelinating peripheral neuropathy in mice, but the mechanism that causes failure of myelin maintenance remained unknown. Here, we report that mTORC1 and c-Jun are continuously activated in the absence of Phb1, likely as part of the SC response to mitochondrial damage. Moreover, we demonstrate that these pathways are involved in the demyelination process, and that inhibition of mTORC1 using rapamycin partially rescues the demyelinating pathology. Therefore, we propose that mTORC1 and c-Jun may play a critical role as executioners of demyelination in the context of perturbations to SC mitochondria.

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Biologic therapy-related demyelinating peripheral neuropathy in a child with juvenile idiopathic arthritis

Journal of Clinical Case reports and reviews ◽

10.36879/jccrr.18.000108 ◽

2018 ◽

pp. 1-2

Keyword(s):

Juvenile Idiopathic Arthritis ◽

Peripheral Neuropathy ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Biologic Therapy ◽

Tnf Inhibitor ◽

Neurological Sequelae ◽

Demyelinating Peripheral Neuropathy ◽

Necrosis Factor ◽

Clinical Worsening

Demyelinating peripheral neuropathy has been described in association with tumor necrosis factor (TNF) inhibitors. It is rarely developed after treatment discontinuation. We present the case of a child with juvenile idiopathic arthritis who developed peripheral neuropathy few months after TNF inhibitor withdrawal with clinical worsening of the neurological sequelae while undergoing treatment with abatacept.

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416-P: Palmitic Acid-Induced Schwann Cells Apoptosis and Oxidative Stress in Diabetes Peripheral Neuropathy

Diabetes ◽

10.2337/db21-416-p ◽

2021 ◽

Vol 70 (Supplement 1) ◽

pp. 416-P

Author(s):

JINGWEN FAN ◽

LIXIN GUO

Keyword(s):

Oxidative Stress ◽

Peripheral Neuropathy ◽

Palmitic Acid ◽

Schwann Cells ◽

Diabetes Peripheral Neuropathy ◽

And Oxidative Stress

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Dedifferentiation of Schwann cells by taxanes participates in the chemotherapy-induced peripheral neuropathy pathogenesis

Proceedings for Annual Meeting of The Japanese Pharmacological Society ◽

10.1254/jpssuppl.93.0_2-s25-2 ◽

2020 ◽

Vol 93 (0) ◽

pp. 2-S25-2

Author(s):

Satoshi Imai

Keyword(s):

Peripheral Neuropathy ◽

Schwann Cells

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Long Non-coding RNA XIST Attenuates Diabetic Peripheral Neuropathy by Inducing Autophagy Through MicroRNA-30d-5p/sirtuin1 Axis

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.655157 ◽

2021 ◽

Vol 8 ◽

Author(s):

Bei-Yan Liu ◽

Lin Li ◽

Li-Wei Bai ◽

Chang-Shui Xu

Keyword(s):

Oxidative Stress ◽

Peripheral Neuropathy ◽

Schwann Cells ◽

Diabetic Peripheral Neuropathy ◽

Beclin 1 ◽

Diabetic Mice ◽

Non Coding Rna ◽

Non Coding Rnas ◽

Long Non Coding Rna

Diabetic peripheral neuropathy (DPN) is a prevalent diabetes mellitus (Feldman et al., 2017) complication and the primary reason for amputation. Meanwhile, long non-coding RNAs (lncRNAs) are a type of regulatory non-coding RNAs (ncRNAs) that broadly participate in DPN development. However, the correlation of lncRNA X-inactive specific transcript (XIST) with DPN remains unclear. In this study, we were interested in the role of XIST in the modulation of DPN progression. Significantly, our data showed that the expression of XIST and sirtuin1 (SIRT1) was inhibited, and the expression of microRNA-30d-5p (miR-30d-5p) was enhanced in the trigeminal sensory neurons of the diabetic mice compared with the normal mice. The levels of LC3II and Beclin-1 were inhibited in the diabetic mice. The treatment of high glucose (HG) reduced the XIST expression in Schwann cells. The apoptosis of Schwann cells was enhanced in the HG-treated cells, but the overexpression of XIST could block the effect in the cells. Moreover, the levels of LC3II and Beclin-1 were reduced in the HG-treated Schwann cells, while the overexpression of XIST was able to reverse this effect. The HG treatment promoted the production of oxidative stress, while the XIST overexpression could attenuate this result in the Schwann cells. Mechanically, XIST was able to sponge miR-30d-5p and miR-30d-5p-targeted SIRT1 in the Schwann cells. MiR-30d-5p inhibited autophagy and promoted oxidative stress in the HG-treated Schwann cells, and SIRT1 presented a reversed effect. MiR-30d-5p mimic or SIRT1 depletion could reverse XIST overexpression-mediated apoptosis and autophagy of the Schwann cells. Thus, we concluded that XIST attenuated DPN by inducing autophagy through miR-30d-5p/SIRT1 axis. XIST and miR-30d-5p may be applied as the potential targets for DPN therapy.

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