PMP22 duplication dysregulates lipid homeostasis and plasma membrane organization in developing human Schwann cells

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216275%3A25310%2F24%3A39922120" target="_blank" >RIV/00216275:25310/24:39922120 - isvavai.cz</a>

Result on the web

<a href="https://academic.oup.com/brain/article/147/9/3113/7672887?login=false" target="_blank" >https://academic.oup.com/brain/article/147/9/3113/7672887?login=false</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1093/brain/awae158" target="_blank" >10.1093/brain/awae158</a>

Result language

angličtina

Original language name

PMP22 duplication dysregulates lipid homeostasis and plasma membrane organization in developing human Schwann cells

Original language description

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. Peripheral nerve insulation requires an intricate relationship between neurons and Schwann cells which is highly dependent on lipids. Prior et al. show how an excess of the PMP22 protein dysregulates the storage of lipids and their incorporation into the plasma membrane of Schwann cells, giving rise to Charcot-Marie-Tooth disease type 1A.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

10400 - Chemical sciences

Project

—

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2024

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Brain

ISSN

0006-8950

e-ISSN

1460-2156

Volume of the periodical

147

Issue of the periodical within the volume

9

Country of publishing house

GB - UNITED KINGDOM

Number of pages

18

Pages from-to

3113-3130

UT code for WoS article

001296119300001

EID of the result in the Scopus database

2-s2.0-85203082256