scholarly journals Enhanced axonal Neuregulin-1 type-III signaling ameliorates disease severity in a CMT1B mouse model

2018 ◽  
Author(s):  
Cristina Scapin ◽  
Cinzia Ferri ◽  
Emanuela Pettinato ◽  
Desiree Zambroni ◽  
Francesca Bianchi ◽  
...  

ABSTRACTCharcot–Marie–Tooth neuropathies (CMTs) are a group of genetic disorders that affect the peripheral nervous system (PNS) 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 CMTs 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 TACE/ADAM17, also ameliorates the neuropathy. Thus, modulation of Nrg1TIII by TACE/ADAM17 inhibition may represent a general treatment for hypomyelinating neuropathies.

2018 ◽  
Vol 28 (6) ◽  
pp. 992-1006 ◽  
Author(s):  
Cristina Scapin ◽  
Cinzia Ferri ◽  
Emanuela Pettinato ◽  
Desiree Zambroni ◽  
Francesca Bianchi ◽  
...  

2018 ◽  
Author(s):  
Belin Sophie ◽  
Francesca Ornaghi ◽  
Ghjuvan'Ghjacumu Shackleford ◽  
Jie Wang ◽  
Cristina Scapin ◽  
...  

Myelin sheath thickness is precisely regulated and essential for rapid propagation of action potentials along myelinated axons. In the peripheral nervous system, extrinsic signals from the axonal protein neuregulin 1 type III regulate Schwann cell fate and myelination. Here we ask if modulating neuregulin 1 type III levels in neurons would restore myelination in a model of congenital hypomyelinating neuropathy (CHN). Using a mouse model of CHN, we rescued the myelination defects by early overexpression of neuregulin 1 type III. Surprisingly, the rescue was independent from the upregulation of Egr2 or essential myelin genes. Rather, we observed the activation of MAPK/ERK and other myelin genes such as peripheral myelin protein 2 (Pmp2) and oligodendrocyte myelin glycoprotein (Omg). We also confirmed that the permanent activation of MAPK/ERK in Schwann cells has detrimental effects on myelination. Our findings demonstrate that the modulation of axon-to-glial neuregulin 1 type III signaling has beneficial effects and restores myelination defects during development in a model of CHN.


2019 ◽  
Vol 28 (13) ◽  
pp. 2282-2282
Author(s):  
Sophie Belin ◽  
Francesca Ornaghi ◽  
Ghjuvan’Ghjacumu Shackleford ◽  
Jie Wang ◽  
Cristina Scapin ◽  
...  

2019 ◽  
Vol 28 (10) ◽  
pp. 1752-1752
Author(s):  
Sophie Belin ◽  
Francesca Ornaghi ◽  
Ghjuvan’Ghjacumu Shackleford ◽  
Jie Wang ◽  
Cristina Scapin ◽  
...  

2018 ◽  
Vol 28 (8) ◽  
pp. 1260-1273 ◽  
Author(s):  
Sophie Belin ◽  
Francesca Ornaghi ◽  
Ghjuvan’Ghjacumu Shackleford ◽  
Jie Wang ◽  
Cristina Scapin ◽  
...  

2018 ◽  
Vol 19 (1) ◽  
pp. 17-25 ◽  
Author(s):  
Liwei Lang ◽  
Austin Y. Shull ◽  
Yong Teng

Coordination between the amplification of the fibroblast growth factor FGF19, overexpression of its corresponding receptor FGFR4, and hyperactivation of the downstream transmembrane enzyme β-klotho has been found to play pivotal roles in mediating tumor development and progression. Aberrant FGF19-FGFR4 signaling has been implicated in driving specific tumorigenic events including cancer cell proliferation, apoptosis resistance, and metastasis by activating a myriad of downstream signaling cascades. As an attractive target, several strategies implemented to disrupt the FGF19-FGFR4 axis have been developed in recent years, and FGF19-FGFR4 binding inhibitors are being intensely evaluated for their clinical use in treating FGF19-FGFR4 implicated cancers. Based on the established work, this review aims to detail how the FGF19-FGFR4 signaling pathway plays a vital role in cancer progression and why disrupting communication between FGF19 and FGFR4 serves as a promising therapeutic strategy for disrupting cancer progression.


2015 ◽  
Vol 77 ◽  
pp. 173-190 ◽  
Author(s):  
R.L. Nosheny ◽  
P.V. Belichenko ◽  
B.L. Busse ◽  
A.M. Weissmiller ◽  
V. Dang ◽  
...  

Author(s):  
Maria Francisca Coutinho ◽  
Marisa Encarnação ◽  
Francisco Laranjeira ◽  
Lúcia Lacerda ◽  
Maria João Prata ◽  
...  

AbstractWhile being well known that the diagnosis of many genetic disorders relies on a combination of clinical suspicion and confirmatory genetic testing, not rarely, however, genetic testing needs much perseverance and cunning strategies to identify the causative mutation(s). Here we present a case of a thorny molecular diagnosis of mucolipidosis type III alpha/beta, which is an autosomal recessive lysosomal storage disorder, caused by a defect in the


2011 ◽  
Vol 52 (7) ◽  
pp. 4369 ◽  
Author(s):  
Kate A. Powell ◽  
Jennifer R. Davies ◽  
Elaine Taylor ◽  
Michael A. Wride ◽  
Marcela Votruba

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