Dysregulated Inflammatory Signaling upon Charcot-Marie-Tooth Type 1C Mutation of SIMPLE Protein

Abstract

Endosomal trafficking is a key mechanism to modulate signal propagation and cross talk. Ubiquitin adaptors, along with endosomal sorting complex required for transport (ESCRT) complexes, are also integrated to terminate ligand-receptor activation in late endosomes and multivesicular bodies (MVBs). Within these pathways, we recently demonstrated that the protein SIMPLE is a novel player in MVB regulation. SIMPLE is also clinically important and its mutation accounts for the Charcot-Marie-Tooth type 1C (CMT1C) disease. MVB defects of mutation and deletion of SIMPLE, however, are distinct. Here, we show that MVB defects found in mutation but not deletion of SIMPLE lead to impaired turnover and accumulation of ESCRT-0 protein Hrs puncta in late endosomes. We further uncover increased colocalization of ubiquitin ligase TRAF6 and Hrs in late endosomes. Upon stimulation with interkeukin-1 or transforming growth factor ␤, prolonged activation of p38 kinase/JNK is detected, while nuclear accumulation of NF-B and phosphorylation of SMAD2 is reduced with CMT1C mutation. The aberrant kinetics we observed in inflammatory signaling may contribute to increased tumor susceptibility and changes in the levels of chemokines/cytokines that result from CMT1C mutation. We propose that altered endosomal trafficking due to malformations of MVBs and subsequent atypical signaling kinetic may account for a toxic gain of function in CMT1C pathogenesis.

The topology, structure and PE interaction of LITAF underpin a Charcot-Marie-Tooth disease type 1C

“…Furthermore, cycloheximide chase experiments in vivo suggested that the V144M construct was degraded more rapidly compared to wild type. It is therefore tempting to speculate that all CMT1C mutations might lead to similar structural alterations within the LITAF domain, resulting in an unstable and toxic interaction with lipid head groups and consequent endocytic membrane disruption [10, 56]. This aberrant association of LITAF with membranes might lead to the dysfunctional trafficking of Schwann cell membrane receptors, including growth factor receptors [9, 57, 58] and cell adhesion molecules [6, 59], with consequent disruption of the critical endocytic pathways that maintain the integrity of peripheral nerve myelin.…”

Calcium Deregulation and Mitochondrial Bioenergetics in GDAP1-Related CMT Disease

“…These studies suggest that GDAP1 acts as a sensor of the reduced to oxidized glutathione ratio (GSH/GSSG) participating in the release of an antioxidative response causing the recovery of GSH/GSSG. These results suggest a possible role of oxidative stress and chronic inflammation in the pathogenesis of GDAP1-related CMT, as shown to occur in other forms of CMT such as CMT1A [30] or CMT1C [31].…”

Melatonin Treatment Reduces Oxidative Damage and Normalizes Plasma Pro-Inflammatory Cytokines in Patients Suffering from Charcot-Marie-Tooth Neuropathy: A Pilot Study in Three Children

“…Axonal degeneration and increased disability occur over time. Among other molecular mechanisms of demyelination in CMT1, oxidative stress, inflammation, autophagy impairment, and mitochondrial dysfunction, have been proposed [ 7 , 8 , 9 , 13 , 14 , 15 , 16 , 42 , 43 ]. Moreover, skeletal muscle atrophy induced by denervation is associated with excessive mitochondrial ROS formation [ 44 ].…”

“…Experimental studies in rats and mice demonstrate an association of peripheral neuropathy with a reduction of the antioxidant status with low levels of GSH, and of glutathione peroxidase (GPx) and reductase (GRd) activities, and an increased lipid peroxidation [ 15 ]. The excess of ROS induces the activation of NF-κB and NF-κB-dependent pro-inflammatory cytokines including IL-1b in CMT patients [ 16 ]. Evidences for macrophage-dependent inflammatory activation and myelin disruption has been shown in a murine model of CMT1A [ 17 ].…”