PFN2 and GAMT as common molecular determinants of axonal Charcot-Marie-Tooth disease

Juneja, Manisha; Azmi, Asfar S.; Baets, Jonathan; Roos, Andreas; Jennings, Matthew J.; Saveri, Paola; Pisciotta, Chiara; Bernard-Marissal, Nathalie; Schneider, Bernard L.; Verfaillie, Catherine M.; Chrast, Roman; Seeman, Pavel; Hahn, Angelika F.; Jonghe, Peter De; Maudsley, Stuart; Horvath, Rita; Pareyson, Davide; Timmerman, Vincent

doi:10.1136/jnnp-2017-317562

Cited by 12 publications

(10 citation statements)

References 26 publications

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“…Only a limited number of groups have worked on MNs derived from hiPSCs in CMT disease, despite the fact that more than 90 genes are involved [43,44]. In the realm of axonal CMT, Saporta et al and Juneja et al studied the NEFL, MFN2, HSPB8, and HSPB1 mutations [11,45]; Ohara et al studied those of MFN2 [46]; and Kim et al studied those of HSPB1 [47], whereas nobody has studied mutations of GDAP1, according to our knowledge. In their protocol, Saporta et al used SMAD signaling inhibition, Shh, and RA [11], obtaining mature spinal MNs in 35 days, as in the protocol of Ohara et al [46].…”

Section: Discussionmentioning

confidence: 99%

Optimized Protocol to Generate Spinal Motor Neuron Cells from Induced Pluripotent Stem Cells from Charcot Marie Tooth Patients

et al. 2020

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Modelling rare neurogenetic diseases to develop new therapeutic strategies is highly challenging. The use of human-induced pluripotent stem cells (hiPSCs) is a powerful approach to obtain specialized cells from patients. For hereditary peripheral neuropathies, such as Charcot–Marie–Tooth disease (CMT) Type II, spinal motor neurons (MNs) are impaired but are very difficult to study. Although several protocols are available to differentiate hiPSCs into neurons, their efficiency is still poor for CMT patients. Thus, our goal was to develop a robust, easy, and reproducible protocol to obtain MNs from CMT patient hiPSCs. The presented protocol generates MNs within 20 days, with a success rate of 80%, using specifically chosen molecules, such as Sonic Hedgehog or retinoic acid. The timing and concentrations of the factors used to induce differentiation are crucial and are given hereby. We then assessed the MNs by optic microscopy, immunocytochemistry (Islet1/2, HB9, Tuj1, and PGP9.5), and electrophysiological recordings. This method of generating MNs from CMT patients in vitro shows promise for the further development of assays to understand the pathological mechanisms of CMT and for drug screening.

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Section: Discussionmentioning

confidence: 99%

Optimized Protocol to Generate Spinal Motor Neuron Cells from Induced Pluripotent Stem Cells from Charcot Marie Tooth Patients

et al. 2020

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“…Human iPSC lines (three clones/genotype) were generated and thoroughly characterized by the Stem Cell Institute, University of Leuven, Belgium as previously described. 8 Most importantly, both patient and control lines were reprogrammed together using Sendai virus reprogramming. IPSCs were maintained on Matrigel ® coated plates (734–1440, VWR Biotechnologies) in Essential 8 TM Flex medium and supplement (A2858501, Thermo Fisher).…”

Section: Methodsmentioning

confidence: 99%

Induced pluripotent stem cell-derived motor neurons of CMT type 2 patients reveal progressive mitochondrial dysfunction

Lent

Verstraelen

Asselbergh

et al. 2021

Brain

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Axonal Charcot-Marie-Tooth neuropathies (CMT type 2) are caused by inherited mutations in various genes functioning in different pathways. The type of genes and multiplicity of mutations reflect the clinical and genetic heterogeneity in CMT2 disease, which complicates the diagnosis and has halted therapy development. 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 demonstrate 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 (DLK) could partially ameliorate the mitochondrial disease phenotypes in CMT2 subtypes. Altogether, our data reveals shared cellular phenotypes across different CMT2 subtypes and suggests that targeting such common pathomechanisms could allow the development of a uniform treatment for CMT2.

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“…1 Biomarkers of peripheral nerve disease have a role in diagnosis, clinical management and in research where much attention is focused on their use in natural history studies and clinical trials. 2,3 They have relevance for a broad range of peripheral nerve diseases including inflammatory neuropathies such as chronic inflammatory demyelinating polyneuropathy (CIDP) and vasculitic neuropathy, toxic neuropathies such as chemotherapy-induced painful neuropathy (CIPN), diabetic neuropathy and also genetic neuropathies such as Charcot-Marie-Tooth disease (CMT) and hereditary TTR amyloidosis (ATTR). This review will primarily focus on the use of blood biomarkers of peripheral neuropathy for clinical management and as outcome measures in clinical trials (See Table 1).…”

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confidence: 99%

Blood biomarkers of peripheral neuropathy

Rossor

2022

Acta Neuro Scandinavica

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Traditionally, neurophysiology is the primary diagnostic and prognostic biomarker in peripheral neuropathy clinical practice; however, it may lack responsiveness in the context of slowly progressive neuropathies and where there is significant axonal damage. The development of ultrasensitive platforms for measuring serum proteins at the lower limit of detection of traditional ELISA techniques has transformed the field of blood biomarkers of peripheral neuropathy. A variety of blood biomarkers have been identified from inflammatory cytokines and apokines in diabetic neuropathy through to neuron‐specific proteins such as neurofilament light chain, Schwann cell‐specific proteins such as TMPRSS5 and microRNAs in other acquired and hereditary neuropathies. In this article, we review blood biomarkers of disease activity for the common subtypes of peripheral neuropathy including inflammatory demyelinating neuropathies, vasculitic neuropathy, diabetic neuropathy, chemotherapy‐induced neuropathy and Charcot–Marie–Tooth disease and related disorders including TTR amyloidosis.

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PFN2 and GAMT as common molecular determinants of axonal Charcot-Marie-Tooth disease

Cited by 12 publications

References 26 publications

Optimized Protocol to Generate Spinal Motor Neuron Cells from Induced Pluripotent Stem Cells from Charcot Marie Tooth Patients

Optimized Protocol to Generate Spinal Motor Neuron Cells from Induced Pluripotent Stem Cells from Charcot Marie Tooth Patients

Induced pluripotent stem cell-derived motor neurons of CMT type 2 patients reveal progressive mitochondrial dysfunction

Blood biomarkers of peripheral neuropathy

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