Publication
Title
Induced pluripotent stem cell-derived motor neurons of CMT type 2 patients reveal progressive mitochondrial dysfunction
Author
Abstract
Axonal Charcot-Marie-Tooth neuropathies (CMT type 2) are caused by inherited mutations in various genes functioning in different pathways. The types of genes and multiplicity of mutations reflect the clinical and genetic heterogeneity in CMT2 disease, which complicates its diagnosis and has inhibited the development of therapies. Here, we used CMT2 patient-derived pluripotent stem cells (iPSCs) to identify common hallmarks of axonal degeneration shared by different CMT2 subtypes. We compared the cellular phenotypes of neurons differentiated from CMT2 patient iPSCs with those from healthy controls and a CRISPR/Cas9-corrected isogenic line. Our results demonstrated neurite network alterations along with extracellular electrophysiological abnormalities in the differentiated motor neurons. Progressive deficits in mitochondrial and lysosomal trafficking, as well as in mitochondrial morphology, were observed in all CMT2 patient lines. Differentiation of the same CMT2 iPSC lines into peripheral sensory neurons only gave rise to cellular phenotypes in subtypes with sensory involvement, supporting the notion that some gene mutations predominantly affect motor neurons. We revealed a common mitochondrial dysfunction in CMT2-derived motor neurons, supported by alterations in the expression pattern and oxidative phosphorylation, which could be recapitulated in the sciatic nerve tissue of a symptomatic mouse model. Inhibition of a dual leucine zipper kinase could partially ameliorate the mitochondrial disease phenotypes in CMT2 subtypes. Altogether, our data reveal shared cellular phenotypes across different CMT2 subtypes and suggests that targeting such common pathomechanisms could allow the development of a uniform treatment for CMT2.
Language
English
Source (journal)
Brain. - London
Publication
London : 2021
ISSN
0006-8950
DOI
10.1093/BRAIN/AWAB226
Volume/pages
144 :8 (2021) , p. 2471-2485
ISI
000710930500032
Pubmed ID
34128983
Full text (Publisher's DOI)
Full text (open access)
UAntwerpen
Faculty/Department
Research group
Project info
Genome and transcriptome engineering with CRISPR/Cas as a precision medicine for Charcot-Marie-Tooth type 2L.
Deep phenotyping of cellular heterogeneity and maturation in human iPSC-derived brain organoids and cardiomyocytes.
Identification of the common signature pathways of axonal degeneration in Charcot-Marie-Tooth neuropathies as a framework to develop therapeutic strategies.
The peripheral component of neurodegeneration: response to and transmission of host-derived and microbial amyloid proteins in the enteric nervous system.
VIB-Integrated European -omics research project for diagnosis and therapy in rare neuromuscular and neurodegenerative diseases (NEUROMICS).
Solving the unsolved Rare Diseases (Solve-Rd).
Transmission Electron Microscope with cryo-ware.
CLCI - High end infrastructure for confocal live cell imaging.
An integrated multi-purpose basic infrastructure for dynamic and sensitive metabolic profiling of cells and embryos.
The peripheral component of neurodegeneration: uptake and transmission of amyloid proteins in the enteric nervous system.
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identifier
Creation 30.08.2021
Last edited 06.01.2025
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