SH3TC2, a protein mutant in Charcot–Marie–Tooth neuropathy, links peripheral nerve myelination to endosomal recycling

Stendel, Claudia; Roos, Andreas; Kleine, H. O.; Arnaud, Estelle; Özçelik, Murat; Sidiropoulos, Paris; Zenker, Jennifer; Schüpfer, Fanny; Lehmann, Ute; Sobota, Radoslaw M.; Litchfield, David W.; Lüscher, Bernhard; Chrast, Roman; Suter, Ueli; Senderek, Jan

doi:10.1093/brain/awq168

Cited by 81 publications

(74 citation statements)

References 48 publications

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“…Because myelin comprises a specially organized membrane sheet, membrane trafficking might play an important role in the establishment of this structure. In the peripheral nervous system, an endosomal recycling pathway involved in polarized membrane trafficking has been associated with Schwann cell myelination (Roberts et al, 2010;Stendel et al, 2010). In addition, axonal signaling regulates myelin thickness (Michailov et al, 2004;Newbern and Birchmeier, 2010), and this signaling might affect polarized membrane trafficking in Schwann cells.…”

Section: Research Articlementioning

confidence: 99%

ARHGEF10 directs the localization of Rab8 to Rab6-positive executive vesicles

Shibata

Kawanai

Hara

et al. 2016

Journal of Cell Science

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The function of ARHGEF10, a known guanine nucleotide exchange factor (GEF) for RhoA with proposed roles in various diseases, is poorly understood. To understand the precise function of this protein, we raised a monoclonal antibody against ARHGEF10 and determined its localization in HeLa cells. ARHGEF10 was found to localize to vesicles containing Rab6 (of which there are three isoforms, Rab6a, Rab6b and Rab6c), Rab8 (of which there are two isoforms, Rab8a and Rab8b), and/or the secretion marker neuropeptide Y (NPY)-Venus in a Rab6-dependent manner. These vesicles were known to originate from the Golgi and contain secreted or membrane proteins. Ectopic expression of an N-terminal-truncated ARHGEF10 mutant led to the generation of large vesicle-like structures containing both Rab6 and Rab8. Additionally, small interfering (si)RNA-mediated knockdown of ARHGEF10 impaired the localization of Rab8 to these exocytotic vesicles. Furthermore, the invasiveness of MDA-MB231 cells was markedly decreased by knockdown of ARHGEF10, as well as of Rab8. From these results, we propose that ARHGEF10 acts in exocytosis and tumor invasion in a Rab8-dependent manner.

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Section: Research Articlementioning

confidence: 99%

ARHGEF10 directs the localization of Rab8 to Rab6-positive executive vesicles

Shibata

Kawanai

Hara

et al. 2016

Journal of Cell Science

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“…Two groups have shown that SH3TC2 preferentially binds the GTP-bound form of small GTPase Rab11 and promotes recycling of internalized transferrin receptors to the cell surface in HeLa cells [77, 78], supporting a function of SH3TC2 as a novel Rab11 effector in the regulation of endosomal recycling. Furthermore, these groups reported that CMT4C-associated mutations abolish the interaction of SH3TC2 with Rab11, causing SH3TC2 mislocalization from recycling endosomes to the cytosol and impaired transferrin receptor recycling in HeLa and HEK293 cells [77, 78]. These findings provide evidence supporting the potential involvement of endosomal recycling dysfunction in the pathogenesis of CMT4C neuropathy.…”

Section: Endosomal Recycling Dysfunctionmentioning

confidence: 99%

Dysregulation of ErbB Receptor Trafficking and Signaling in Demyelinating Charcot-Marie-Tooth Disease

Lee

Chin

2016

Mol Neurobiol

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Charcot-Marie-Tooth (CMT) disease is the most common inherited peripheral neuropathy with the majority of cases involving demyelination of peripheral nerves. The pathogenic mechanisms of demyelinating CMT remain unclear, and no effective therapy currently exists for this disease. The discovery that mutations in different genes can cause a similar phenotype of demyelinating peripheral neuropathy raises the possibility that there may be convergent mechanisms leading to demyelinating CMT pathogenesis. Increasing evidence indicates that ErbB receptor-mediated signaling plays a major role in the control of Schwann cell-axon communication and myelination in the peripheral nervous system. Recent studies reveal that several demyelinating CMT-linked proteins are novel regulators of endocytic trafficking and/or phosphoinositide metabolism that may affect ErbB receptor signaling. Emerging data have begun to suggest that dysregulation of ErbB receptor trafficking and signaling in Schwann cells may represent a common pathogenic mechanism in multiple subtypes of demyelinating CMT. In this review, we focus on the roles of ErbB receptor trafficking and signaling in regulation of peripheral nerve myelination and discuss the emerging evidence supporting the potential involvement of altered ErbB receptor trafficking and signaling in demyelinating CMT pathogenesis and the possibility of modulating these trafficking and signaling processes for treating demyelinating peripheral neuropathy.

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“…High cholesterol availability is known to be required for myelin membrane growth (Saher et al, 2005). In addition, studies in other CMT neuropathies have emphasized the importance of endocytic pathways in the formation of myelin Roberts et al, 2010;Sidiropoulos et al, 2012;Stendel et al, 2010;Verhoeven et al, 2003), reinforcing a link between NDRG1 function in endocytic trafficking and myelin formation/ maintenance. NDRG1 might also affect oligodendrocyte differentiation, as suggested by the lack of outgrowths and downregulation of Olig2 in Ndrg1-silenced oligodendrocytes.…”

Section: Ndrg1 and Cmt4dmentioning

confidence: 99%

NDRG1 functions in LDL receptor trafficking by regulating endosomal recycling and degradation

Pietiäinen

Vassilev

Blom

et al. 2013

Journal of Cell Science

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Summary N-myc downstream-regulated gene 1 (NDRG1) mutations cause Charcot-Marie-Tooth disease type 4D (CMT4D). However, the cellular function of NDRG1 and how it causes CMT4D are poorly understood. We report that NDRG1 silencing in epithelial cells results in decreased uptake of low-density lipoprotein (LDL) due to reduced LDL receptor (LDLR) abundance at the plasma membrane. This is accompanied by the accumulation of LDLR in enlarged EEA1-positive endosomes that contain numerous intraluminal vesicles and sequester ceramide. Concomitantly, LDLR ubiquitylation is increased but its degradation is reduced and ESCRT (endosomal sorting complex required for transport) proteins are downregulated. Co-depletion of IDOL (inducible degrader of the LDLR), which ubiquitylates the LDLR and promotes its degradation, rescues plasma membrane LDLR levels and LDL uptake. In murine oligodendrocytes, Ndrg1 silencing not only results in reduced LDL uptake but also in downregulation of the oligodendrocyte differentiation factor Olig2. Both phenotypes are rescued by co-silencing of Idol, suggesting that ligand uptake through LDLR family members controls oligodendrocyte differentiation. These findings identify NDRG1 as a novel regulator of multivesicular body formation and endosomal LDLR trafficking. The deficiency of functional NDRG1 in CMT4D might impair lipid processing and differentiation of myelinating cells.

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SH3TC2, a protein mutant in Charcot–Marie–Tooth neuropathy, links peripheral nerve myelination to endosomal recycling

Cited by 81 publications

References 48 publications

ARHGEF10 directs the localization of Rab8 to Rab6-positive executive vesicles

ARHGEF10 directs the localization of Rab8 to Rab6-positive executive vesicles

Dysregulation of ErbB Receptor Trafficking and Signaling in Demyelinating Charcot-Marie-Tooth Disease

NDRG1 functions in LDL receptor trafficking by regulating endosomal recycling and degradation

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