Loss of <scp>YAP</scp> in Schwann cells improves <scp>HNPP</scp> pathophysiology

Moore, Seth M.; Jeong, Eunbi; Zahid, Muhammad; Gawron, Joseph; Arora, Simar; Belin, Sophie; Sim, Fraser; Poitelon, Yannick; Feltri, M. Laura

doi:10.1002/glia.24592

Cited by 2 publications

References 47 publications

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Pharmacologically increasing cGMP improves proteostasis and reduces neuropathy in mouse models of CMT1

Moore,

Gawron,

Stevens

et al. 2024

Cell. Mol. Life Sci.

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Increasing cyclic GMP activates 26S proteasomes via phosphorylation by Protein Kinase G and stimulates the intracellular degradation of misfolded proteins. Therefore, agents that raise cGMP may be useful therapeutics against neurodegenerative diseases and other diseases in which protein degradation is reduced and misfolded proteins accumulate, including Charcot Marie Tooth 1A and 1B peripheral neuropathies, for which there are no treatments. Here we increased cGMP in the S63del mouse model of CMT1B by treating for three weeks with either the phosphodiesterase 5 inhibitor tadalafil, or the brain-penetrant soluble guanylyl cyclase stimulator CYR119. Both molecules activated proteasomes in the affected peripheral nerves, reduced polyubiquitinated proteins, and improved myelin thickness and nerve conduction. CYR119 increased cGMP more than tadalafil in the peripheral nerves of S63del mice and elicited greater biochemical and functional improvements. To determine whether raising cGMP could be beneficial in other neuropathies, we first showed that polyubiquitinated proteins and the disease-causing protein accumulate in the sciatic nerves of the C3 mouse model of CMT1A. Treatment of these mice with CYR119 reduced the levels of polyubiquitinated proteins and the disease-causing protein, presumably by increasing their degradation, and improved myelination, nerve conduction, and motor coordination. Thus, pharmacological agents that increase cGMP are promising treatments for CMT1 neuropathies and may be useful against other proteotoxic and neurodegenerative diseases.

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Pharmacologically increasing cGMP improves proteostasis and reduces neuropathy in mouse models of CMT1

Moore,

Gawron,

Stevens

et al. 2024

Cell. Mol. Life Sci.

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The STRIPAK complex is required for radial sorting and laminin receptor expression in Schwann cells

Weaver,

Shkoruta,

Pellegatta

et al. 2024

Preprint

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During peripheral nervous system development, Schwann cells undergo Rac1-dependent cytoskeletal reorganization as they insert cytoplasmic extensions into axon bundles to radially sort, ensheath, and myelinate individual axons. However, our understanding of the direct effectors targeted by Rac1 is limited. Here, we demonstrate that striatin-3 and MOB4 are novel Rac1 interactors. We show that, similar to Rac1-null Schwann cells, Schwann cell specific ablation of striatin-3 causes defects in lamellipodia formation. In addition, conditional Schwann cell knockout of multiple striatin proteins presents a severe delay in radial sorting. Finally, we demonstrate here that deletion of Rac1 or striatin-1/3 in Schwann cells causes defects in Hippo pathway regulation, phosphorylation of the Hippo pathway effectors YAP and TAZ, and expression of genes co-regulated by YAP and TAZ, such as extracellular matrix receptors. In summary, our results indicate that striatin-3 is a novel Rac1 interactor, show that striatin proteins are required for peripheral nervous system development, and reveal a role for Rac1 in regulation of the Hippo pathway in Schwann cells.

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Loss of YAP in Schwann cells improves HNPP pathophysiology

Cited by 2 publications

References 47 publications

Pharmacologically increasing cGMP improves proteostasis and reduces neuropathy in mouse models of CMT1

Pharmacologically increasing cGMP improves proteostasis and reduces neuropathy in mouse models of CMT1

The STRIPAK complex is required for radial sorting and laminin receptor expression in Schwann cells

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