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Rab7 mutants associated with Charcot-Marie-Tooth disease exhibit enhanced NGF-stimulated signaling.

ABSTRACT: Missense mutants in the late endosomal Rab7 GTPase cause the autosomal dominant peripheral neuropathy Charcot-Marie-Tooth disease type 2B (CMT2B). As yet, the pathological mechanisms connecting mutant Rab7 protein expression to altered neuronal function are undefined. Here, we analyze the effects Rab7 CMT2B mutants on nerve growth factor (NGF) dependent intracellular signaling in PC12 cells. The nerve growth factor receptor TrkA interacted similarly with Rab7 wild-type and CMT2B mutant proteins, but the mutant proteins significantly enhanced TrkA phosphorylation in response to brief NGF stimulation. Two downstream signaling pathways (Erk1/2 and Akt) that are directly activated in response to phospho-TrkA were differentially affected. Akt signaling, arising in response to activated TrkA at the plasma membrane was unaffected. However Erk1/2 phosphorylation, triggered on signaling endosomes, was increased. Cytoplasmic phospho-Erk1/2 persisted at elevated levels relative to control samples for up to 24 h following NGF stimulation. Nuclear shuttling of phospho Erk1/2, which is required to induce MAPK phosphatase expression and down regulate signaling, was greatly reduced by the Rab7 CMT2B mutants and explains the previously reported inhibition in PC12 neurite outgrowth. In conclusion, the data demonstrate a mechanistic link between Rab7 CMT2B mutants and altered TrkA and Erk1/2 signaling from endosomes.

SUBMITTER: BasuRay S

PROVIDER: S-EPMC3000344 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Charcot Marie Tooth 2B Peripheral Sensory Neuropathy: How Rab7 Mutations Impact NGF Signaling?

Project description:Charcot-Marie-Tooth 2B peripheral sensory neuropathy (CMT2B) is a debilitating autosomal dominant hereditary sensory neuropathy. Patients with this disease lose pain sensation and frequently need amputation. Axonal dysfunction and degeneration of peripheral sensory neurons is a major clinical manifestation of CMT2B. However, the cellular and molecular pathogenic mechanisms remain undefined. CMT2B is caused by missense point mutations (L129F, K157N, N161T/I, V162M) in Rab7 GTPase. Strong evidence suggests that the Rab7 mutation(s) enhances the cellular levels of activated Rab7 proteins, thus resulting in increased lysosomal activity and autophagy. As a consequence, trafficking and signaling of neurotrophic factors such as nerve growth factor (NGF) in the long axons of peripheral sensory neurons are particularly vulnerable to premature degradation. A "gain of toxicity" model has, thus, been proposed based on these observations. However, studies of fly photo-sensory neurons indicate that the Rab7 mutation(s) causes a "loss of function", resulting in haploinsufficiency. In the review, we summarize experimental evidence for both hypotheses. We argue that better models (rodent animals and human neurons) of CMT2B are needed to precisely define the disease mechanisms.

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Rab7 mutants associated with Charcot-Marie-Tooth disease cause delayed growth factor receptor transport and altered endosomal and nuclear signaling.

Project description:Rab7 belongs to the Ras superfamily of small GTPases and is a master regulator of early to late endocytic membrane transport. Four missense mutations in the late endosomal Rab7 GTPase (L129F, K157N, N161T, and V162M) cause the autosomal dominant peripheral neuropathy Charcot-Marie-Tooth type 2B (CMT2B) disease. As yet, the pathological mechanisms connecting mutant Rab7 protein expression to altered neuronal function are undefined. Here, we analyze the effects of Rab7 CMT2B mutants on epidermal growth factor (EGF)-dependent intracellular signaling and trafficking. Three different cell lines expressing Rab7 CMT2B mutants and stimulated with EGF exhibited delayed trafficking of EGF to LAMP1-positive late endosomes and lysosomes and slowed EGF receptor (EGFR) degradation. Expression of all Rab7 CMT2B mutants altered the Rab7 activation cycle, leading to enhanced and prolonged EGFR signaling as well as variable increases in p38 and ERK1/2 activation. However, due to reduced nuclear translocation of p38 and ERK1/2, the downstream nuclear activation of Elk-1 was decreased along with the expression of immediate early genes like c-fos and Egr-1 by the disease mutants. In conclusion, our results demonstrate that Rab7 CMT2B mutants impair growth factor receptor trafficking and, in turn, alter p38 and ERK1/2 signaling from perinuclear, clustered signaling endosomes. The resulting down-regulation of EGFR-dependent nuclear transcription that is crucial for normal axon outgrowth and peripheral innervation offers a crucial new mechanistic insight into disease pathogenesis that is relevant to other neurodegenerative diseases.

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Charcot-Marie-Tooth disease.

Project description:Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of genetic disorders presenting with the phenotype of a chronic progressive neuropathy affecting both the motor and sensory nerves. During the last decade over two dozen genes have been identified in which mutations cause CMT. The disease illustrates a multitude of genetic principles, including diverse mutational mechanisms from point mutations to copy number variation (CNV), allelic heterogeneity, age-dependent penetrance and variable expressivity. Population based studies have determined the contributions of the various genes to disease burden enabling evidence-based approaches to genetic testing.

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Project description:Charcot-Marie-Tooth (CMT) disease is a common neurogenetic disorder and its heterogeneity is a challenge for genetic diagnostics. The genetic diagnostic procedures for a CMT patient can be explored according to the electrophysiological criteria: very slow motor nerve conduction velocity (MNCV) (<15 m/s), slow MNCV (15-25 m/s), intermediate MNCV (25-45 m/s), and normal MNCV (>45 m/s). Based on the inheritance pattern, intermediate CMT can be divided into dominant (DI-CMT) and recessive types (RI-CMT). GJB1 is currently considered to be associated with X-linked DI-CMT, and MPZ, INF2, DNM2, YARS, GNB4, NEFL, and MFN2 are associated with autosomal DI-CMT. Moreover, GDAP1, KARS, and PLEKHG5 are associated with RI-CMT. Identification of these genes is not only important for patients and families but also provides new information about pathogenesis. It is hoped that this review will lead to a better understanding of intermediate CMT and provide a detailed diagnostic procedure for intermediate CMT.

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Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot-Marie-Tooth type 2B neuropathy.

Project description:Charcot-Marie-Tooth type 2B (CMT2B) is clinically characterized by marked distal muscle weakness and wasting and a high frequency of foot ulcers, infections, and amputations of the toes because of recurrent infections. CMT2B maps to chromosome 3q13-q22. We refined the CMT2B locus to a 2.5-cM region and report two missense mutations (Leu129Phe and Val162Met) in the small GTP-ase late endosomal protein RAB7 which causes the CMT2B phenotype in three extended families and in three patients with a positive family history. The alignment of RAB7 orthologs shows that both missense mutations target highly conserved amino acid residues. RAB7 is ubiquitously expressed, and we found expression in sensory and motor neurons.

| S-EPMC1180247 | biostudies-literature

Charcot-Marie-Tooth: From Molecules to Therapy.

Project description:Charcot-Marie-Tooth (CMT) is the most prevalent category of inherited neuropathy. The most common inheritance pattern is autosomal dominant, though there also are X-linked and autosomal recessive subtypes. In addition to a variety of inheritance patterns, there are a myriad of genes associated with CMT, reflecting the heterogeneity of this disorder. Next generation sequencing (NGS) has expanded and simplified the diagnostic yield of genes/molecules underlying and/or associated with CMT, which is of paramount importance in providing a substrate for current and future targeted disease-modifying treatment options. Considerable research attention for disease-modifying therapy has been geared towards the most commonly encountered genetic mutations (PMP22, GJB1, MPZ, and MFN2). In this review, we highlight the clinical background, molecular understanding, and therapeutic investigations of these CMT subtypes, while also discussing therapeutic research pertinent to the remaining less common CMT subtypes.

| S-EPMC6679156 | biostudies-literature

Expression data from a Charcot-Marie-Tooth 1B neuropathy mouse model

Project description:We have generated mouse models of real CMT1B mutations in the gene encoding for myelin protein zero (P0). One of these mutants, P0S63del is retained in the ER where it elicits an unfolded protein response (UPR). Genetic ablation of the UPR factor CHOP restores the motor capacity in S63del mice. We used microarray to decipher the molecular mechanism undelying the P0S63del neuropathy and the rescue in S63del/Chop null nerves. Sciatic nerves were dissected from WT, S63del, Chop null and S63del/Chop null mice at three different time points: (i) postnatal day 5 (P5) when myelination has just started and only the primary effects of the presence of the mutant protein should be detected; (ii) P28, around the peak of myelination, when all the downstream targets of CHOP should be activated; and (iii) 4 months, to check for secondary effects of the disease and because this was the time-point when the motor and morphological rescue due to the ablation of CHOP were clearly detectable.

2013-05-01 | E-GEOD-40610 | biostudies-arrayexpress

Genetics of Charcot-Marie-Tooth Disease

Project description:Genetics of Charcot-Marie-Tooth Disease

| PRJNA382008 | ENA

Charcot-Marie-Tooth disease-associated mutants of GDAP1 dissociate its roles in peroxisomal and mitochondrial fission.

Project description:Mitochondria and peroxisomes can be fragmented by the process of fission. The fission machineries of both organelles share a set of proteins. GDAP1 is a tail-anchored protein of mitochondria and induces mitochondrial fragmentation. Mutations in GDAP1 lead to Charcot-Marie-Tooth disease (CMT), an inherited peripheral neuropathy, and affect mitochondrial dynamics. Here, we show that GDAP1 is also targeted to peroxisomes mediated by the import receptor Pex19. Knockdown of GDAP1 leads to peroxisomal elongation that can be rescued by re-expressing GDAP1 and by missense mutated forms found in CMT patients. GDAP1-induced peroxisomal fission is dependent on the integrity of its hydrophobic domain 1, and on Drp1 and Mff, as is mitochondrial fission. Thus, GDAP1 regulates mitochondrial and peroxisomal fission by a similar mechanism. However, our results reveal also a more critical role of the amino-terminal GDAP1 domains, carrying most CMT-causing mutations, in the regulation of mitochondrial compared to peroxisomal fission.

| S-EPMC3674444 | biostudies-literature

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

Project description: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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