期刊
HUMAN MOLECULAR GENETICS
卷 28, 期 6, 页码 992-1006出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddy411
关键词
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资金
- National Institute of Health [R01 NS55256, R56NS096104]
- Charcot-Marie-Tooth Association
- Fondazione Telethon [GPP10007, GGP14147, GGP15012]
- Italian Ministry of Health [GR-2011-02346791]
- Umberto Veronesi Foundation
- Deutsche Forschungsgemeinschaft (DFG)
- DFG research grant [SCHW741/4-1]
Charcot-Marie-Tooth (CMT) neuropathies are a group of genetic disorders that affect the peripheral nervous system with heterogeneous pathogenesis and no available treatment. Axonal neuregulin 1 type III (Nrg1TIII) drives peripheral nerve myelination by activating downstream signaling pathways such as PI3K/Akt and MAPK/Erk that converge on master transcriptional regulators of myelin genes, such as Krox20. We reasoned that modulating Nrg1TIII activity may constitute a general therapeutic strategy to treat CMT5 that are characterized by reduced levels of myelination. Here we show that genetic overexpression of Nrg1TIII ameliorates neurophysiological and morphological parameters in a mouse model of demyelinating CMT1B, without exacerbating the toxic gain-of-function that underlies the neuropathy. Intriguingly, the mechanism appears not to be related to Krox20 or myelin gene upregulation, but rather to a beneficial rebalancing in the stoichiometry of myelin lipids and proteins. Finally, we provide proof of principle that stimulating Nrg1TIII signaling, by pharmacological suppression of the Nrg1TIII inhibitor tumor necrosis factor-alpha-converting enzyme (TACE/ADAM17), also ameliorates the neuropathy. Thus, modulation of Nrg1TIII by TACE/ADAM17 inhibition may represent a general treatment for hypomyelinating neuropathies.
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