PMP22 overexpression causes dysmyelination in mice

Abstract

Charcot-Marie-Tooth (CMT) disease is the most frequent hereditary peripheral neuropathy in humans. Its prevalence is about one in 2500. A subform, CMT1A, is transmitted as an autosomal dominant trait. An estimated 75% of patients are affected. This disorder has been shown to be associated with the duplication of a 1.5 Mb region of the short arm of chromosome 17, in which the PMP22 gene has been mapped. We have constructed a murine model of CMT1A by inserting into the murine genome a human YAC containing peripheral myelin protein 22 (PMP22) and its flanking controlling elements. We describe the behaviour of the C22 line (seven copies of YAC, 2.1 times PMP22 overexpression) during the myelination process. Electron microscopy, morphometry, electrophysiology, nerve conduction and expression of specific markers (e.g. Krox20) in normal and pathological Schwann cells demonstrated that PMP22 overexpression leads to a defect in the myelination of axons. The largest axons are the most affected. Only a few demyelination/remyelination processes were observed. Moreover, PMP22 overexpression probably enhances collagen synthesis by fibroblasts, before myelination, demonstrating that structures other than Schwann cells are affected by PMP22 overexpression. Classically, CMT1A was thought to be induced by a demyelination process following a phase of normal myelination, yet our data suggest that dysmyelination should be considered as a major factor for the disease.

Peripheral Myelin Protein 22 Is in Complex with α6β4 Integrin, and Its Absence Alters the Schwann Cell Basal Lamina

“…3, 4). These abnormalities are in agreement with data from young PMP22-deficient (Adlkofer et al, 1995) and PMP22 overexpressor (Magyar et al, 1996;Robaglia-Schlupp et al, 2002) mice. In nerves of PMP22-deficient and overproducer mice, prominent pockets of basal laminas surrounding hypomyelinated axons were also described previously (Magyar et al, 1996;Adlkofer et al, 1997), but the molecular mechanisms underlying these changes were not addressed.…”

PMP22 antisense oligonucleotides reverse Charcot-Marie-Tooth disease type 1A features in rodent models

“…We therefore performed 3′ mRNA poly-A + sequencing (RNA-seq) on sciatic nerves of a separate cohort of naive 5-week-old C22 versus WT littermates (C22 5-week and WT 5-week) and a cohort of C22 and WT littermates that were treated with either PBS or ASO1 at 100 mg/ kg weekly for 9 weeks (C22 PBS 15-week and C22 ASO1 15-week). Using variance-model-based differential expression analysis, we determined 2,080 differentially expressed genes (DEGs) with a fold change greater than 2 at a false discovery rate (FDR) of 0.00001 or less in 5-week-old C22 versus WT mice and 1,056 DEGs in 15-week-old C22 versus WT mice that had been treated [29][30][31][32][33], ASO-mediated reduction of PMP22 mRNA levels markedly improves and even reverses several neuropathy end points, such as motor, electrophysiology, pathology, and transcriptomic changes. Independent studies of the CMT1A rat model, a well-characterized model of CMT1A (12,34), show that ASOs suppress Pmp22 mRNA levels in several affected nerves and restore myelination and electrophysiological properties of motor axons.…”

Cell transplantation strategies for acquired and inherited disorders of peripheral myelin

“…The most common cause of CMT is from duplication of a 1.4 Mb segment on chromosome 17p11.2 harboring the PMP22 gene (CMT 1A), found in about 50% of all patients with CMT 8, 9, 10. Although the precise disease mechanism is not clear, it is suspected that overproduction of the PMP22 protein by the extra gene copy leads to abnormal Schwann cell development and myelin sheath maintenance, ultimately resulting in secondary axon loss and loss of sensory and motor function 11, 12. CMT is typically not life‐threatening but the patients’ symptoms impact their quality of life profoundly, and there is no effective treatment 7, 13.…”