4 results on '"Vlek N"'
Search Results
2. PMP22 duplication dysregulates lipid homeostasis and plasma membrane organization in developing human Schwann cells.
- Author
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Prior R, Silva A, Vangansewinkel T, Idkowiak J, Tharkeshwar AK, Hellings TP, Michailidou I, Vreijling J, Loos M, Koopmans B, Vlek N, Agaser C, Kuipers TB, Michiels C, Rossaert E, Verschoren S, Vermeire W, de Laat V, Dehairs J, Eggermont K, van den Biggelaar D, Bademosi AT, Meunier FA, vandeVen M, Van Damme P, Mei H, Swinnen JV, Lambrichts I, Baas F, Fluiter K, Wolfs E, and Van Den Bosch L
- Subjects
- Humans, Animals, Mice, Sciatic Nerve metabolism, Gene Duplication, Schwann Cells metabolism, Myelin Proteins metabolism, Myelin Proteins genetics, Charcot-Marie-Tooth Disease genetics, Charcot-Marie-Tooth Disease metabolism, Charcot-Marie-Tooth Disease pathology, Homeostasis physiology, Lipid Metabolism physiology, Cell Membrane metabolism, Induced Pluripotent Stem Cells metabolism
- Abstract
Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited peripheral neuropathy caused by a 1.5 Mb tandem duplication of chromosome 17 harbouring the PMP22 gene. This dose-dependent overexpression of PMP22 results in disrupted Schwann cell myelination of peripheral nerves. To obtain better insights into the underlying pathogenic mechanisms in CMT1A, we investigated the role of PMP22 duplication in cellular homeostasis in CMT1A mouse models and in patient-derived induced pluripotent stem cells differentiated into Schwann cell precursors (iPSC-SCPs). We performed lipidomic profiling and bulk RNA sequencing (RNA-seq) on sciatic nerves of two developing CMT1A mouse models and on CMT1A patient-derived iPSC-SCPs. For the sciatic nerves of the CMT1A mice, cholesterol and lipid metabolism was downregulated in a dose-dependent manner throughout development. For the CMT1A iPSC-SCPs, transcriptional analysis unveiled a strong suppression of genes related to autophagy and lipid metabolism. Gene ontology enrichment analysis identified disturbances in pathways related to plasma membrane components and cell receptor signalling. Lipidomic analysis confirmed the severe dysregulation in plasma membrane lipids, particularly sphingolipids, in CMT1A iPSC-SCPs. Furthermore, we identified reduced lipid raft dynamics, disturbed plasma membrane fluidity and impaired cholesterol incorporation and storage, all of which could result from altered lipid storage homeostasis in the patient-derived CMT1A iPSC-SCPs. Importantly, this phenotype could be rescued by stimulating autophagy and lipolysis. We conclude that PMP22 duplication disturbs intracellular lipid storage and leads to a more disordered plasma membrane owing to an alteration in the lipid composition, which might ultimately lead to impaired axo-glial interactions. Moreover, targeting lipid handling and metabolism could hold promise for the treatment of patients with CMT1A., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)
- Published
- 2024
- Full Text
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3. The systemic inhibition of the terminal complement system reduces neuroinflammation but does not improve motor function in mouse models of CMT1A with overexpressed PMP22 .
- Author
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Michailidou I, Vreijling J, Rumpf M, Loos M, Koopmans B, Vlek N, Straat N, Agaser C, Kuipers TB, Mei H, Baas F, and Fluiter K
- Abstract
Charcot-Marie-Tooth disease type 1A (CMT1A) is the most prevalent hereditary demyelinating neuropathy. This autosomal, dominantly inherited disease is caused by a duplication on chromosome 17p which includes the peripheral myelin protein 22 (PMP22) gene. There is clinical evidence that the disability in CMT1A is to a large extend due to axonal damage rather than demyelination. Over-expression of PMP22 is recently thought to impede cholesterol trafficking causing a total shutdown of local cholesterol and lipid synthesis in the Schwann cells, thus disturbing their ability to remyelinate. But there is a large variety in disease burden between CMT1A patients with the same genetic defect, indicating the presence of modifying factors that affect disease severity. One of these potential factors is the immune system. Several reports have described patients with co-occurrence of CMT1A with chronic inflammatory demyelinating disease or Guillain-Barré syndrome. We have previously shown in multiple animal models that the innate immune system and specifically the terminal complement system is a driver of inflammatory demyelination. To test the contribution of the terminal complement system to neuroinflammation and disease progression in CMT1A, we inhibited systemic complement C6 in two transgenic mouse models for CMT1A, the C3- PMP22 and C3- PMP22 c-JunP0Cre models. Both models over-express human PMP22 , and one (C3- PMP22 c-JunP0Cre) also has a Schwann cell-specific knockout of c-Jun, a crucial regulator of myelination controlling autophagy. We found that systemic inhibition of C6 using antisense oligonucleotides affects the neuroinflammation, Rho GTPase and ERK/MAPK signalling pathways in the CMT1A mouse models. The cholesterol synthesis pathway remained unaffected. Analysis of motor function during treatment with C6 antisense oligonucleotides did not reveal any significant improvement in the CMT1A mouse models. This study shows that the contribution of the terminal complement system to progressive loss of motor function in the CMT1A mouse models tested is limited., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Frank Baas reports a relationship with Complement Pharma BV that includes: board membership. Kees Fluiter reports a relationship with Complement Pharma BV that includes: consulting or advisory. Maarten Loos reports a relationship with Synaptologics BV that includes: employment. Bastijn Koopmans reports a relationship with Synaptologics BV that includes: employment. Nina Vlek reports a relationship with Synaptologics BV that includes: employment. Nina Straat reports a relationship with Synaptologics BV that includes: employment. Frank Baas has patent Complement inhibition for improved nerve regeneration issued to Regenesance BV. Frank Baas has patent COMPLEMENT ANTAGONISTS AND USES THEREOF issued to Regenesance BV. Kees Fluiter has patent COMPLEMENT ANTAGONISTS AND USES THEREOF issued to Regenesance BV. Frank Baas has patent #ANTIBODIES THAT BIND HUMAN C6 AND USES THEREOF issued to Regenesance BV., (© 2023 The Authors.)
- Published
- 2023
- Full Text
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4. Cortical and spinal somatosensory evoked potentials in patients suffering from lumbosacral disc prolapse.
- Author
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Notermans SL and Vlek NM
- Subjects
- Adolescent, Adult, Cerebral Cortex physiology, Cerebral Cortex physiopathology, Electromyography, Female, Humans, Intervertebral Disc Displacement physiopathology, Lumbar Vertebrae diagnostic imaging, Lumbar Vertebrae physiopathology, Male, Middle Aged, Radiography, Sacrum diagnostic imaging, Sacrum physiopathology, Spinal Nerve Roots diagnostic imaging, Spinal Nerve Roots physiology, Spinal Nerve Roots physiopathology, Evoked Potentials, Somatosensory, Intervertebral Disc Displacement diagnosis
- Published
- 1988
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