Soluble neuregulin-1 modulates disease pathogenesis in rodent models of Charcot-Marie-Tooth disease 1A

摘要: Duplication of the gene encoding peripheral myelin protein 22 kDa (PMP22) underlies most common inherited neuropathy, Charcot-Marie-Tooth 1A (CMT1A), a disease without known cure. Although demyelination represents characteristic feature, clinical phenotype CMT1A is determined by degree axonal loss, and patients suffer from progressive muscle weakness impaired sensation. manifests within first two decades life, walking disabilities, foot deformities electrophysiological abnormalities are already present in childhood. Here, we show Pmp22-transgenic rodent models that Schwann cells acquire persistent differentiation defect during early postnatal development, caused imbalanced activity PI3K-Akt Mek-Erk signaling pathways. We demonstrate enhanced axonally overexpressed neuregulin-1 (NRG1) type I drives diseased toward preserves nerve axons. Notably, preclinical experimental therapy using rat model, when treatment restricted to soluble NRG1 effectively overcomes development restores axon survival into adulthood. Our findings suggest model which cell limited time window crucial for long-term maintenance support.