keyword
https://read.qxmd.com/read/37759799/regulation-of-endosomal-trafficking-by-rab7-and-its-effectors-in-neurons-clues-from-charcot-marie-tooth-2b-disease
#1
REVIEW
Ryan J Mulligan, Bettina Winckler
Intracellular endosomal trafficking controls the balance between protein degradation and synthesis, i.e., proteostasis, but also many of the cellular signaling pathways that emanate from activated growth factor receptors after endocytosis. Endosomal trafficking, sorting, and motility are coordinated by the activity of small GTPases, including Rab proteins, whose function as molecular switches direct activity at endosomal membranes through effector proteins. Rab7 is particularly important in the coordination of the degradative functions of the pathway...
September 16, 2023: Biomolecules
https://read.qxmd.com/read/35851620/mitochondria-dysfunction-in-charcot-marie-tooth-2b-peripheral-sensory-neuropathy
#2
JOURNAL ARTICLE
Yingli Gu, Flora Guerra, Mingzheng Hu, Alexander Pope, Kijung Sung, Wanlin Yang, Simone Jetha, Thomas A Shoff, Tessanya Gunatilake, Owen Dahlkamp, Linda Zhixia Shi, Fiore Manganelli, Maria Nolano, Yue Zhou, Jianqing Ding, Cecilia Bucci, Chengbiao Wu
Rab7 GTPase regulates mitochondrial morphology and function. Missense mutation(s) of Rab7 underlies the pathogenesis of Charcot Marie Tooth 2B (CMT2B) peripheral neuropathy. Herein, we investigate how mitochondrial morphology and function are impacted by the CMT2B associated Rab7V162M mutation. In contrast to recent studies of using heterologous overexpression systems, our results demonstrate significant mitochondrial fragmentation in both human CMT2B patient fibroblasts and CMT2B embryonic fibroblasts (MEFs)...
July 18, 2022: Communications Biology
https://read.qxmd.com/read/34486665/tubular-microdomains-of-rab7-positive-endosomes-retrieve-trka-a-mechanism-disrupted-in-charcot-marie-tooth-disease-2b
#3
JOURNAL ARTICLE
Ronja Markworth, Vivian Dambeck, Lars Malte Steinbeck, Angeliki Koufali, Bastian Bues, Tal M Dankovich, Carolin Wichmann, Katja Burk
Axonal survival and growth requires signalling from tropomyosin receptor kinases (Trks). To transmit their signals, receptor-ligand complexes are endocytosed and undergo retrograde trafficking to the soma, where downstream signalling occurs. Vesicles transporting neurotrophic receptors to the soma are reported to be Rab7-positive late endosomes and/or multivesicular bodies (MVBs), where receptors localize within so-called intraluminal vesicles (herein Rab7 corresponds to Rab7A unless specified otherwise). Therefore, one challenging question is how downstream signalling is possible given the insulating properties of intraluminal vesicles...
October 15, 2021: Journal of Cell Science
https://read.qxmd.com/read/32829064/an-altered-lipid-metabolism-characterizes-charcot-marie-tooth-type-2b-peripheral-neuropathy
#4
JOURNAL ARTICLE
Anna Maria Giudetti, Flora Guerra, Serena Longo, Raffaella Beli, Roberta Romano, Fiore Manganelli, Maria Nolano, Vincenzo Mangini, Lucio Santoro, Cecilia Bucci
Charcot-Marie Tooth type 2B (CMT2B) is a rare inherited peripheral neuropathy caused by five missense mutations in the RAB7A gene, which encodes a small GTPase of the RAB family. Currently, no cure is available for this disease. In this study, we approached the disease by comparing the lipid metabolism of CMT2B-derived fibroblasts to that of healthy controls. We found that CMT2B cells showed increased monounsaturated fatty acid level and increased expression of key enzymes of monounsaturated and polyunsaturated fatty acid synthesis...
August 20, 2020: Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids
https://read.qxmd.com/read/32326241/charcot-marie-tooth-type-2b-a-new-phenotype-associated-with-a-novel-rab7a-mutation-and-inhibited-egfr-degradation
#5
JOURNAL ARTICLE
Paola Saveri, Maria De Luca, Veronica Nisi, Chiara Pisciotta, Roberta Romano, Giuseppe Piscosquito, Mary M Reilly, James M Polke, Tiziana Cavallaro, Gian Maria Fabrizi, Paola Fossa, Elena Cichero, Raffaella Lombardi, Giuseppe Lauria, Stefania Magri, Franco Taroni, Davide Pareyson, Cecilia Bucci
The rare autosomal dominant Charcot-Marie-Tooth type 2B (CMT2B) is associated with mutations in the RAB7A gene, involved in the late endocytic pathway. CMT2B is characterized by predominant sensory loss, ulceromutilating features, with lesser-to-absent motor deficits. We characterized clinically and genetically a family harboring a novel pathogenic RAB7A variant and performed structural and functional analysis of the mutant protein. A 39-year-old woman presented with early-onset walking difficulties, progressive distal muscle wasting and weakness in lower limbs and only mild sensory signs...
April 21, 2020: Cells
https://read.qxmd.com/read/32280996/alteration-of-the-late-endocytic-pathway-in-charcot-marie-tooth-type-2b-disease
#6
JOURNAL ARTICLE
Roberta Romano, Cristina Rivellini, Maria De Luca, Rossana Tonlorenzi, Raffaella Beli, Fiore Manganelli, Maria Nolano, Lucio Santoro, Eeva-Liisa Eskelinen, Stefano C Previtali, Cecilia Bucci
The small GTPase RAB7A regulates late stages of the endocytic pathway and plays specific roles in neurons, controlling neurotrophins trafficking and signaling, neurite outgrowth and neuronal migration. Mutations in the RAB7A gene cause the autosomal dominant Charcot-Marie-Tooth type 2B (CMT2B) disease, an axonal peripheral neuropathy. As several neurodegenerative diseases are caused by alterations of endocytosis, we investigated whether CMT2B-causing mutations correlate with changes in this process. To this purpose, we studied the endocytic pathway in skin fibroblasts from healthy and CMT2B individuals...
January 2021: Cellular and Molecular Life Sciences: CMLS
https://read.qxmd.com/read/31231042/lysosomal-regulation-of-inter-mitochondrial-contact-fate-and-motility-in-charcot-marie-tooth-type-2
#7
JOURNAL ARTICLE
Yvette C Wong, Wesley Peng, Dimitri Krainc
Properly regulated mitochondrial networks are essential for cellular function and implicated in multiple diseases. Mitochondria undergo fission and fusion events, but the dynamics and regulation of a third event of inter-mitochondrial contact formation remain unclear. Using super-resolution imaging, we demonstrate that inter-mitochondrial contacts frequently form and play a fundamental role in mitochondrial networks by restricting mitochondrial motility. Inter-mitochondrial contact untethering events are marked and regulated by mitochondria-lysosome contacts, which are modulated by RAB7 GTP hydrolysis...
August 5, 2019: Developmental Cell
https://read.qxmd.com/read/29130394/alterations-of-autophagy-in-the-peripheral-neuropathy-charcot-marie-tooth-type-2b
#8
JOURNAL ARTICLE
David Colecchia, Mariangela Stasi, Margherita Leonardi, Fiore Manganelli, Maria Nolano, Bianca Maria Veneziani, Lucio Santoro, Eeva-Liisa Eskelinen, Mario Chiariello, Cecilia Bucci
Charcot-Marie-Tooth type 2B (CMT2B) disease is a dominant axonal peripheral neuropathy caused by 5 mutations in the RAB7A gene, a ubiquitously expressed GTPase controlling late endocytic trafficking. In neurons, RAB7A also controls neuronal-specific processes such as NTF (neurotrophin) trafficking and signaling, neurite outgrowth and neuronal migration. Given the involvement of macroautophagy/autophagy in several neurodegenerative diseases and considering that RAB7A is fundamental for autophagosome maturation, we investigated whether CMT2B-causing mutants affect the ability of this gene to regulate autophagy...
2018: Autophagy
https://read.qxmd.com/read/28165391/charcot-marie-tooth-2b-peripheral-sensory-neuropathy-how-rab7-mutations-impact-ngf-signaling
#9
REVIEW
Harry Liu, Chengbiao Wu
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...
February 4, 2017: International Journal of Molecular Sciences
https://read.qxmd.com/read/27462242/factors-affecting-phenotype-variability-in-a-family-with-cmt2b-gender-and-lrsam1-genotype
#10
Leema Reddy Peddareddygari, Kinsi Oberoi, Jaasrini Reddy Vellore, Raji P Grewal
Charcot-Marie-Tooth disease type 2 (CMT2) is an autosomal dominant axonal neuropathy caused by mutations in various genes. The subtype CMT2B results from missense mutations in RAB7A, member RAS oncogene family gene, whereas missense mutations in the Leucine-rich repeat and sterile alpha motif-containing protein 1 (LRSAM1) gene cause CMT2P. We describe the genotype/phenotype analysis of a family in which a previously described mutation in the RAB7A gene and a novel mutation in the LRSAM1 gene were identified...
May 2016: Case Reports in Neurology
https://read.qxmd.com/read/26791407/charcot-marie-tooth-2b-associated-rab7-mutations-cause-axon-growth-and-guidance-defects-during-vertebrate-sensory-neuron-development
#11
JOURNAL ARTICLE
Olga Y Ponomareva, Kevin W Eliceiri, Mary C Halloran
BACKGROUND: Charcot-Marie-Tooth2b (CMT2b) is an axonal form of a human neurodegenerative disease that preferentially affects sensory neurons. CMT2b is dominantly inherited and is characterized by unusually early onset, presenting in the second or third decade of life. Five missense mutations in the gene encoding Rab7 GTPase have been identified as causative in human CMT2b disease. Although several studies have modeled CMT2b disease in cultured neurons and in Drosophila, the mechanisms by which defective Rab7 leads to disease remain poorly understood...
January 20, 2016: Neural Development
https://read.qxmd.com/read/26362287/charcot-marie-tooth-disease-new-insights-from-skin-biopsy
#12
JOURNAL ARTICLE
Fiore Manganelli, Maria Nolano, Chiara Pisciotta, Vincenzo Provitera, Gian M Fabrizi, Tiziana Cavallaro, Annamaria Stancanelli, Giuseppe Caporaso, Michael E Shy, Lucio Santoro
OBJECTIVE: To evaluate, by skin biopsy, dermal nerve fibers in 31 patients with 3 common Charcot-Marie-Tooth (CMT) genotypes (CMT1A, late-onset CMT1B, and CMTX1), and rarer forms of CMT caused by mutations in RAB7 (CMT2B), TRPV4 (CMT2C), and GDAP1 (AR-CMT2K) genes. METHODS: We investigated axonal loss by quantifying Meissner corpuscles and intrapapillary myelinated endings and evaluated morphometric changes in myelinated dermal nerve fibers by measuring fiber caliber, internodal, and nodal gap length...
October 6, 2015: Neurology
https://read.qxmd.com/read/24521780/human-rab7-mutation-mimics-features-of-charcot-marie-tooth-neuropathy-type-2b-in-drosophila
#13
JOURNAL ARTICLE
Katrien Janssens, Sofie Goethals, Derek Atkinson, Biljana Ermanoska, Erik Fransen, Albena Jordanova, Michaela Auer-Grumbach, Bob Asselbergh, Vincent Timmerman
Charcot-Marie-Tooth disease type 2B (CMT2B) is an inherited axonal peripheral neuropathy. It is characterised by prominent sensory loss, often complicated by severe ulcero-mutilations of toes or feet, and variable motor involvement. Missense mutations in RAB7A, the gene encoding the small GTPase Rab7, cause CMT2B and increase Rab7 activity. Rab7 is ubiquitously expressed and is involved in degradation through the lysosomal pathway. In the neurons, Rab7 plays a role in the long-range retrograde transport of signalling endosomes in the axons...
May 2014: Neurobiology of Disease
https://read.qxmd.com/read/24513337/a-novel-rab7-mutation-in-a-chinese-family-with-charcot-marie-tooth-type-2b-disease
#14
Xing Wang, Chunmao Han, Wenqiang Liu, Ping Wang, Xianqin Zhang
Charcot-Marie-Tooth type 2B (CMT2B) disease is a hereditary motor and sensory neuropathy subtype characterized by prominent loss of sensation, distal muscle weakness and wasting skin ulcers. Recurrent ulcers often require amputation of lower limbs. To date, only four mutations of the RAB7 gene, which encodes the small GTPase, have been associated with CMT2B. A Chinese family with CMT2B was characterzied, Direct DNA sequencing performed on the affected individuals in this family revealed a novel mutation (p...
October 26, 2013: Gene
https://read.qxmd.com/read/24498653/a-novel-rab7-mutation-in-a-chinese-family-with-charcot-marie-tooth-type-2b-disease
#15
JOURNAL ARTICLE
Xing Wang, Chunmao Han, Wenqiang Liu, Ping Wang, Xianqin Zhang
Charcot–Marie–Tooth type 2B (CMT2B) disease is a hereditary motor and sensory neuropathy subtype characterized by prominent loss of sensation, distal muscle weakness and wasting skin ulcers. Recurrent ulcers often require amputation of lower limbs. To date, only four mutations of the RAB7 gene, which encodes the small GTPase, have been associated with CMT2B. A Chinese family with CMT2B was identified. Direct DNA sequencing performed on the affected individuals in this family revealed a novel mutation (p...
January 25, 2014: Gene
https://read.qxmd.com/read/24327558/charcot-marie-tooth-2b-mutations-in-rab7-cause-dosage-dependent-neurodegeneration-due-to-partial-loss-of-function
#16
JOURNAL ARTICLE
Smita Cherry, Eugene Jennifer Jin, Mehmet Neset Ozel, Zhiyuan Lu, Egemen Agi, Dong Wang, Wei-Hung Jung, Daniel Epstein, Ian A Meinertzhagen, Chih-Chiang Chan, P Robin Hiesinger
The small GTPase Rab7 is a key regulator of endosomal maturation in eukaryotic cells. Mutations in rab7 are thought to cause the dominant neuropathy Charcot-Marie-Tooth 2B (CMT2B) by a gain-of-function mechanism. Here we show that loss of rab7, but not overexpression of rab7 CMT2B mutants, causes adult-onset neurodegeneration in a Drosophila model. All CMT2B mutant proteins retain 10-50% function based on quantitative imaging, electrophysiology, and rescue experiments in sensory and motor neurons in vivo. Consequently, expression of CMT2B mutants at levels between 0...
December 10, 2013: ELife
https://read.qxmd.com/read/23616551/defective-axonal-transport-of-rab7-gtpase-results-in-dysregulated-trophic-signaling
#17
JOURNAL ARTICLE
Kai Zhang, Rotem Fishel Ben Kenan, Yasuko Osakada, Wei Xu, Rachel S Sinit, Liang Chen, Xiaobei Zhao, Jia-Yun Chen, Bianxiao Cui, Chengbiao Wu
Retrograde trophic signaling of nerve growth factor (NGF) supports neuronal survival and differentiation. Dysregulated trophic signaling could lead to various neurological disorders. Charcot-Marie-Tooth type 2B (CMT2B) is one of the most common inherited peripheral neuropathies characterized by severe terminal axonal loss. Genetic analysis of human CMT2B patients has revealed four missense point mutations in Rab7, a small GTPase that regulates late endosomal/lysosomal pathways, but the exact pathological mechanism remains poorly understood...
April 24, 2013: Journal of Neuroscience
https://read.qxmd.com/read/23188822/rab7-mutants-associated-with-charcot-marie-tooth-disease-cause-delayed-growth-factor-receptor-transport-and-altered-endosomal-and-nuclear-signaling
#18
JOURNAL ARTICLE
Soumik BasuRay, Sanchita Mukherjee, Elsa G Romero, Matthew N J Seaman, Angela Wandinger-Ness
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...
January 11, 2013: Journal of Biological Chemistry
https://read.qxmd.com/read/23179371/charcot-marie-tooth-type-2b-disease-causing-rab7a-mutant-proteins-show-altered-interaction-with-the-neuronal-intermediate-filament-peripherin
#19
JOURNAL ARTICLE
Laura Cogli, Cinzia Progida, Claire L Thomas, Bradley Spencer-Dene, Claudia Donno, Giampietro Schiavo, Cecilia Bucci
Charcot-Marie-Tooth type 2B (CMT2B) is a peripheral ulcero-mutilating neuropathy caused by four missense mutations in the rab7a gene. CMT2B is clinically characterized by prominent sensory loss, distal muscle weakness leading to muscle atrophy, high frequency of foot ulcers and infections that often results in toe amputations. RAB7A is a ubiquitous small GTPase, which controls transport to late endocytic compartments. Although the biochemical and functional properties of disease-causing RAB7A mutant proteins have been investigated, it is not yet clear how the disease originates...
February 2013: Acta Neuropathologica
https://read.qxmd.com/read/23176482/molecular-basis-of-charcot-marie-tooth-type-2b-disease
#20
JOURNAL ARTICLE
Cecilia Bucci, Maria De Luca
CMT2B (Charcot-Marie-Tooth type 2B) disease is an autosomal dominant peripheral neuropathy whose onset is in the second or third decade of life, thus in adolescence or young adulthood. CMT2B is clinically characterized by severe symmetric distal sensory loss, reduced tendon reflexes at ankles, weakness in the lower limbs and muscle atrophy, complicated by ulcerations that often lead to amputations. Four missense mutations in the gene encoding the small GTPase Rab7 cause the CMT2B neuropathy. Rab7 is a ubiquitous protein that regulates transport to late endosomes and lysosomes in the endocytic pathway...
December 1, 2012: Biochemical Society Transactions
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