RESUMEN
Acetaminophen (APAP)-induced liver injury (AILI) is a common liver disease in clinical practice. Only one clinically approved drug, N-acetylcysteine (NAC), for the treatment of AILI is available in clinics, but novel treatment strategies are still needed due to the complicated pathological changes of AILI and the side effects of NAC. Here, we found that astaxanthin (ASX) can prevent AILI through the Nrf2/HO-1 pathway. After treatment with ASX, there was a positive activation of the Nrf2/HO-1 pathway in AILI models both in vivo and in vitro accompanied by enhanced autophagy and reduced ferroptosis. In APAP-challenged L02 liver cells, ASX reduced autophagy and enhanced apoptosis of the cells. Furthermore, we developed ASX-loaded hollow mesoporous silica nanoparticles (HMSN@ASX) to improve the aqueous solubility of ASX and targeted delivery of ASX to the liver and then significantly improve the therapeutic effects. Taken together, we found that ASX can protect against AILI by activating the Nrf2/HO-1 pathway, which mainly affects oxidative stress, autophagy, and ferroptosis processes, and the HMSN@ASX nanosystem can target the liver to enhance the treatment efficiency of AILI.
Asunto(s)
Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Enfermedad Hepática Inducida por Sustancias y Drogas , Ferroptosis , Neuropatía Hereditaria Motora y Sensorial , Acetaminofén/metabolismo , Acetilcisteína , Autofagia , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/patología , Hemo-Oxigenasa 1/metabolismo , Neuropatía Hereditaria Motora y Sensorial/tratamiento farmacológico , Neuropatía Hereditaria Motora y Sensorial/metabolismo , Neuropatía Hereditaria Motora y Sensorial/patología , Humanos , Hígado/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Dióxido de Silicio/farmacología , XantófilasRESUMEN
Neuro-muscular disorders include a variety of diseases induced by genetic mutations resulting in muscle weakness and waste, swallowing and breathing difficulties. However, muscle alterations and nerve depletions involve specific molecular and cellular mechanisms which lead to the loss of motor-nerve or skeletal-muscle function, often due to an excessive cell death. Morphological and molecular studies demonstrated that a high number of these disorders seem characterized by an upregulated apoptosis which significantly contributes to the pathology. Cell death involvement is the consequence of some cellular processes that occur during diseases, including mitochondrial dysfunction, protein aggregation, free radical generation, excitotoxicity and inflammation. The latter represents an important mediator of disease progression, which, in the central nervous system, is known as neuroinflammation, characterized by reactive microglia and astroglia, as well the infiltration of peripheral monocytes and lymphocytes. Some of the mechanisms underlying inflammation have been linked to reactive oxygen species accumulation, which trigger mitochondrial genomic and respiratory chain instability, autophagy impairment and finally neuron or muscle cell death. This review discusses the main inflammatory pathways contributing to cell death in neuro-muscular disorders by highlighting the main mechanisms, the knowledge of which appears essential in developing therapeutic strategies to prevent the consequent neuron loss and muscle wasting.
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Apoptosis/genética , Neuropatía Hereditaria Motora y Sensorial/metabolismo , Enfermedad de la Neurona Motora/metabolismo , Enfermedades Musculares/metabolismo , Distrofias Musculares/metabolismo , Enfermedades de la Unión Neuromuscular/metabolismo , Astrocitos/metabolismo , Astrocitos/patología , Autofagia/genética , Citocinas/genética , Citocinas/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Regulación de la Expresión Génica , Neuropatía Hereditaria Motora y Sensorial/genética , Neuropatía Hereditaria Motora y Sensorial/patología , Humanos , Inflamación , Microglía/metabolismo , Microglía/patología , Mitocondrias/metabolismo , Mitocondrias/patología , Enfermedad de la Neurona Motora/genética , Enfermedad de la Neurona Motora/patología , Enfermedades Musculares/genética , Enfermedades Musculares/patología , Distrofias Musculares/genética , Distrofias Musculares/patología , FN-kappa B/genética , FN-kappa B/metabolismo , Enfermedades de la Unión Neuromuscular/genética , Enfermedades de la Unión Neuromuscular/patología , Neuronas/metabolismo , Neuronas/patología , Transducción de SeñalRESUMEN
Development of peripheral nervous system (PNS) myelin involves a coordinated series of events between growing axons and the Schwann cell (SC) progenitors that will eventually ensheath them. Myelin sheaths have evolved out of necessity to maintain rapid impulse propagation while accounting for body space constraints. However, myelinating SCs perform additional critical functions that are required to preserve axonal integrity including mitigating energy consumption by establishing the nodal architecture, regulating axon caliber by organizing axonal cytoskeleton networks, providing trophic and potentially metabolic support, possibly supplying genetic translation materials and protecting axons from toxic insults. The intermediate steps between the loss of these functions and the initiation of axon degeneration are unknown but the importance of these processes provides insightful clues. Prevalent demyelinating diseases of the PNS include the inherited neuropathies Charcot-Marie-Tooth Disease, Type 1 (CMT1) and Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) and the inflammatory diseases Acute Inflammatory Demyelinating Polyneuropathy (AIDP) and Chronic Inflammatory Demyelinating Polyneuropathy (CIDP). Secondary axon degeneration is a common feature of demyelinating neuropathies and this process is often correlated with clinical deficits and long-lasting disability in patients. There is abundant electrophysiological and histological evidence for secondary axon degeneration in patients and rodent models of PNS demyelinating diseases. Fully understanding the involvement of secondary axon degeneration in these diseases is essential for expanding our knowledge of disease pathogenesis and prognosis, which will be essential for developing novel therapeutic strategies.
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Axones/metabolismo , Enfermedades Desmielinizantes/metabolismo , Degeneración Nerviosa/metabolismo , Polineuropatías/metabolismo , Animales , Artrogriposis/metabolismo , Artrogriposis/patología , Axones/patología , Enfermedad de Charcot-Marie-Tooth/metabolismo , Enfermedad de Charcot-Marie-Tooth/patología , Enfermedades Desmielinizantes/patología , Neuropatía Hereditaria Motora y Sensorial/metabolismo , Neuropatía Hereditaria Motora y Sensorial/patología , Humanos , Degeneración Nerviosa/patología , Polineuropatías/patología , Células de Schwann/metabolismo , Células de Schwann/patologíaAsunto(s)
Proteínas de Unión al ADN/metabolismo , Lóbulo Frontal/metabolismo , Neuropatía Hereditaria Motora y Sensorial/metabolismo , Proteínas/metabolismo , Médula Espinal/metabolismo , Lóbulo Temporal/metabolismo , Adulto , Encéfalo/metabolismo , Encéfalo/patología , Lóbulo Frontal/patología , Neuropatía Hereditaria Motora y Sensorial/patología , Humanos , Masculino , Fosforilación , Médula Espinal/patología , Lóbulo Temporal/patologíaRESUMEN
Schwann cells are the nerve ensheathing cells of the peripheral nervous system. Absence, loss and malfunction of Schwann cells or their myelin sheaths lead to peripheral neuropathies such as Charcot-Marie-Tooth disease in humans. During Schwann cell development and myelination chromatin is dramatically modified. However, impact and functional relevance of these modifications are poorly understood. Here, we analyzed histone H2B monoubiquitination as one such chromatin modification by conditionally deleting the Rnf40 subunit of the responsible E3 ligase in mice. Rnf40-deficient Schwann cells were arrested immediately before myelination or generated abnormally thin, unstable myelin, resulting in a peripheral neuropathy characterized by hypomyelination and progressive axonal degeneration. By combining sequencing techniques with functional studies we show that H2B monoubiquitination does not influence global gene expression patterns, but instead ensures selective high expression of myelin and lipid biosynthesis genes and proper repression of immaturity genes. This requires the specific recruitment of the Rnf40-containing E3 ligase by Egr2, the central transcriptional regulator of peripheral myelination, to its target genes. Our study identifies histone ubiquitination as essential for Schwann cell myelination and unravels new disease-relevant links between chromatin modifications and transcription factors in the underlying regulatory network.
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Proteína 2 de la Respuesta de Crecimiento Precoz/fisiología , Neuropatía Hereditaria Motora y Sensorial/metabolismo , Histonas/metabolismo , Sistema Nervioso Periférico/metabolismo , Células de Schwann/metabolismo , Animales , Línea Celular Tumoral , Células HEK293 , Humanos , Ratones , Ratones Transgénicos , Sistema Nervioso Periférico/patología , Ratas , Células de Schwann/patología , Ubiquitina-Proteína Ligasas/genética , UbiquitinaciónRESUMEN
Copy number variation of the peripheral nerve myelin gene Peripheral Myelin Protein 22 (PMP22) causes multiple forms of inherited peripheral neuropathy. The duplication of a 1.4 Mb segment surrounding this gene in chromosome 17p12 (c17p12) causes the most common form of Charcot-Marie-Tooth disease type 1A, whereas the reciprocal deletion of this gene causes a separate neuropathy termed hereditary neuropathy with liability to pressure palsies (HNPP). PMP22 is robustly induced in Schwann cells in early postnatal development, and several transcription factors and their cognate regulatory elements have been implicated in coordinating the gene's proper expression. We previously found that a distal super-enhancer domain was important for Pmp22 expression in vitro, with particular impact on a Schwann cell-specific alternative promoter. Here, we investigate the consequences of deleting this super-enhancer in vivo. We find that loss of the super-enhancer in mice reduces Pmp22 expression throughout development and into adulthood, with greater impact on the Schwann cell-specific promoter. Additionally, these mice display tomacula formed by excessive myelin folding, a pathological hallmark of HNPP, as have been previously observed in heterozygous Pmp22 mice as well as sural biopsies from patients with HNPP. Our findings demonstrate a mechanism by which smaller copy number variations, not including the Pmp22 gene, are sufficient to reduce gene expression and phenocopy a peripheral neuropathy caused by the HNPP-associated deletion encompassing PMP22.
Asunto(s)
Artrogriposis/genética , Enfermedad de Charcot-Marie-Tooth/genética , Elementos de Facilitación Genéticos/genética , Neuropatía Hereditaria Motora y Sensorial/genética , Proteínas de la Mielina/genética , Adulto , Animales , Artrogriposis/metabolismo , Artrogriposis/patología , Enfermedad de Charcot-Marie-Tooth/metabolismo , Enfermedad de Charcot-Marie-Tooth/patología , Variaciones en el Número de Copia de ADN/genética , Neuropatía Hereditaria Motora y Sensorial/metabolismo , Neuropatía Hereditaria Motora y Sensorial/patología , Heterocigoto , Humanos , Ratones , Vaina de Mielina/genética , Vaina de Mielina/metabolismo , Nervios Periféricos/metabolismo , Nervios Periféricos/patología , Fenotipo , Células de Schwann/metabolismo , Células de Schwann/patologíaRESUMEN
Distal hereditary motor neuropathies (dHMN) are a group of inherited peripheral nerve disorders characterized by length-dependent motor neuron weakness and subsequent muscle atrophy. Missense mutations in the gene encoding small heat shock protein HSPB1 (HSP27) have been associated with hereditary neuropathies including dHMN. HSPB1 is a member of the small heat shock protein (sHSP) family characterized by a highly conserved α-crystallin domain that is critical to their chaperone activity. In this study, we modeled HSPB1 mutant-induced neuropathies in Drosophila using a human HSPB1S135F mutant that has a missense mutation in its α-crystallin domain. Overexpression of the HSPB1 mutant produced no significant defect in the Drosophila development, however, a partial reduction in the life span was observed. Further, the HSPB1 mutant gene induced an obvious loss of motor activity when expressed in Drosophila neurons. Moreover, suppression of histone deacetylase 6 (HDAC6) expression, which has critical roles in HSPB1 mutant-induced axonal defects, successfully rescued the motor defects in the HSPB1 mutant Drosophila model.
Asunto(s)
Drosophila melanogaster/genética , Proteínas de Choque Térmico/genética , Neuropatía Hereditaria Motora y Sensorial/genética , Chaperonas Moleculares/genética , Animales , Modelos Animales de Enfermedad , Proteínas de Choque Térmico/metabolismo , Neuropatía Hereditaria Motora y Sensorial/metabolismo , Humanos , Chaperonas Moleculares/metabolismo , Actividad Motora/genética , Mutación , alfa-Cristalinas/genética , alfa-Cristalinas/metabolismoRESUMEN
BACKGROUND: Charcot-Marie-Tooth diseases (CMT) are due to abnormalities of many genes, the most frequent being linked to PMP22 (Peripheral Myelin Protein 22). In the past, only spontaneous genetic anomalies occurring in mouse mutants such as Trembler (Tr) mice were available; more recently, several rodent models have been generated for exploration of the pathophysiological mechanisms underlying these neuropathies. METHODS: Based on the personal experience of our team, we describe here the pathological hallmarks of most of these animal models and compare them to the pathological features observed in some CMT patient nerves (CMT types 1A and E; hereditary neuropathy with liability to pressure palsies, HNPP). RESULTS: We describe clinical data and detailed pathological analysis mainly by electron microscopy of the sciatic nerves of these animal models conducted in our laboratory; lesions of PMP22 deficient animals (KO and mutated PMP22) and PMP22 overexpressed models are described and compared to ultrastructural anomalies of nerve biopsies from CMT patients due to PMP22 gene anomalies. It is of note that while there are some similarities, there are also significant differences between the lesions in animal models and human cases. Such observations highlight the complex roles played by PMP22 in nerve development. CONCLUSION: It should be borne in mind that we require additional correlations between animal models of hereditary neuropathies and CMT patients to rationalize the development of efficient drugs.
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Enfermedad de Charcot-Marie-Tooth/genética , Modelos Animales de Enfermedad , Neuropatía Hereditaria Motora y Sensorial/genética , Proteínas de la Mielina/genética , Animales , Enfermedad de Charcot-Marie-Tooth/metabolismo , Enfermedad de Charcot-Marie-Tooth/patología , Enfermedades Desmielinizantes/genética , Enfermedades Desmielinizantes/metabolismo , Enfermedades Desmielinizantes/patología , Expresión Génica , Neuropatía Hereditaria Motora y Sensorial/metabolismo , Neuropatía Hereditaria Motora y Sensorial/patología , Humanos , Ratones , Proteínas de la Mielina/biosíntesis , Mutación Puntual/genética , Ratas , RoedoresRESUMEN
Peripheral myelin protein 22 (PMP22) is a component of compact myelin in the peripheral nervous system. The amount of PMP22 in myelin is tightly regulated, and PMP22 over or under-expression cause Charcot-Marie-Tooth 1A (CMT1A) and Hereditary Neuropathy with Pressure Palsies (HNPP). Despite the importance of PMP22, its function remains largely unknown. It was reported that PMP22 interacts with the ß4 subunit of the laminin receptor α6ß4 integrin, suggesting that α6ß4 integrin and laminins may contribute to the pathogenesis of CMT1A or HNPP. Here we asked if the lack of α6ß4 integrin in Schwann cells influences myelin stability in the HNPP mouse model. Our data indicate that PMP22 and ß4 integrin may not interact directly in myelinating Schwann cells, however, ablating ß4 integrin delays the formation of tomacula, a characteristic feature of HNPP. In contrast, ablation of integrin ß4 worsens nerve conduction velocities and non-compact myelin organization in HNPP animals. This study demonstrates that indirect interactions between an extracellular matrix receptor and a myelin protein influence the stability and function of myelinated fibers.
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Artrogriposis/metabolismo , Neuropatía Hereditaria Motora y Sensorial/metabolismo , Integrina alfa6beta4/metabolismo , Células de Schwann/metabolismo , Animales , Artrogriposis/patología , Neuropatía Hereditaria Motora y Sensorial/patología , Ratones , Ratones Noqueados , Proteínas de la Mielina/metabolismo , Vaina de Mielina/metabolismo , Vaina de Mielina/patología , Células de Schwann/patologíaRESUMEN
In several neurodegenerative diseases in which misfolded proteins accumulate there is impairment of the ubiquitin proteasome system (UPS). We tested if a similar disruption of proteostasis occurs in hereditary peripheral neuropathies. In sciatic nerves from mouse models of two human neuropathies, Myelin Protein Zero mutation (S63del) and increased copy number (P0 overexpression), polyubiquitinated proteins accumulated, and the overall rates of protein degradation were decreased. 26S proteasomes affinity-purified from sciatic nerves of S63del mice were defective in degradation of peptides and a ubiquitinated protein, unlike proteasomes from P0 overexpression, which appeared normal. Nevertheless, cellular levels of 26S proteasomes were increased in both, through the proteolytic-activation of the transcription factor Nrf1, as occurs in response to proteasome inhibitors. In S63del, increased amounts of the deubiquitinating enzymes USP14, UCH37, and USP5 were associated with proteasomes, the first time this has been reported in a human disease model. Inhibitors of USP14 increased the rate of protein degradation in S63del sciatic nerves and unexpectedly increased the phosphorylation of eIF2α by Perk. Thus, proteasome content, composition and activity are altered in these diseases and USP14 inhibitors have therapeutic potential in S63del neuropathy.
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Neuropatía Hereditaria Motora y Sensorial/genética , Neuropatía Hereditaria Motora y Sensorial/metabolismo , Complejo de la Endopetidasa Proteasomal/fisiología , Proteolisis , Nervio Ciático/metabolismo , Animales , Femenino , Neuropatía Hereditaria Motora y Sensorial/patología , Masculino , Ratones , Ratones Transgénicos , Nervio Ciático/patología , Ubiquitina Tiolesterasa/biosíntesis , Ubiquitina Tiolesterasa/genéticaRESUMEN
Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is caused by a heterozygous mutation (P285L) in Tropomyosin-receptor kinase Fused Gene (TFG), histopathologically characterized by progressive spinal motor neuron loss with TFG cytosolic aggregates. Although the TFG protein, found as a type of fusion oncoprotein, is known to facilitate vesicle transport from endoplasmic reticulum (ER) to Golgi apparatus at ER exit site, it is unclear how mutant TFG causes motor neuron degeneration. Here we generated induced pluripotent stem cells (iPSCs) from HMSN-P patients, and differentiated the iPSCs into neural cells with spinal motor neurons (iPS-MNs). We found that HMSN-P patient iPS-MNs exhibited ubiquitin proteasome system (UPS) impairment, and HMSN-P patient iPS-MNs were vulnerable to UPS inhibitory stress. Gene correction of the mutation in TFG using the CRISPR-Cas9 system reverted the cellular phenotypes of HMSN-P patient iPS-MNs. Collectively, these results suggest that our cellular model with defects in cellular integrity including UPS impairments may lead to identification of pathomechanisms and a therapeutic target for HMSN-P.
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Neuropatía Hereditaria Motora y Sensorial/metabolismo , Neuropatía Hereditaria Motora y Sensorial/patología , Células Madre Pluripotentes Inducidas/metabolismo , Neuronas/metabolismo , Neuronas/patología , Complejo de la Endopetidasa Proteasomal/metabolismo , Anciano , Anciano de 80 o más Años , Diferenciación Celular , Células Clonales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neuronas Motoras/patología , Mutación/genética , Fenotipo , Proteínas/genética , Médula Espinal/patologíaRESUMEN
BACKGROUND: The PMP22 gene encodes a protein integral to peripheral myelin. Its deletion leads to hereditary neuropathy with liability to pressure palsies (HNPP). PMP22 is not expressed in the adult central nervous system, but previous studies suggest a role in CNS myelin development. The objective of this study was to identify potential structural and functional alterations in the afferent visual system in HNPP patients. METHODS: Twenty HNPP patients and 18 matched healthy controls (HC) were recruited in a cross-sectional study. Participants underwent neurological examination including visual acuity, visual evoked potential (VEP) examination, optical coherence tomography (OCT), and magnetic resonance imaging with calculation of brain atrophy, regarding grey and white matter, and voxel based morphometry (VBM), in addition answered the National Eye Institute's 39-item Visual Functioning Questionnaire (NEI-VFQ). Thirteen patients and 6 HC were additionally examined with magnetic resonance spectroscopy (MRS). RESULTS: All patients had normal visual acuity, but reported reduced peripheral vision in comparison to HC in the NEI-VFQ (p = 0.036). VEP latency was prolonged in patients (P100 = 103.7±5.7 ms) in comparison to healthy subjects (P100 = 99.7±4.2 ms, p = 0.007). In OCT, peripapillary retinal nerve fiber layer thickness RNFL was decreased in the nasal sector (90.0±15.5 vs. 101.8±16.5, p = 0.013), and lower nasal sector RNFL correlated with prolonged VEP latency (Rho = -0.405, p = 0.012). MRS revealed reduced tNAA (731.4±45.4 vs. 814.9±62.1, p = 0.017) and tCr (373.8±22.2 vs. 418.7±31.1, p = 0.002) in the visual cortex in patients vs. HC. Whole brain volume, grey and white matter volume, VBM and metabolites in a MRS sensory cortex control voxel did not differ significantly between patients and HC. CONCLUSION: PMP22 deletion leads to functional, metabolic and macro-structural alterations in the afferent visual system of HNPP patients. Our data suggest a functional relevance of these changes for peripheral vision, which warrants further investigation and confirmation.
Asunto(s)
Artrogriposis/patología , Neuropatía Hereditaria Motora y Sensorial/patología , Proteínas de la Mielina/genética , Vías Visuales/fisiopatología , Adulto , Artrogriposis/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/fisiología , Estudios de Casos y Controles , Estudios Transversales , Potenciales Evocados Visuales/fisiología , Femenino , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/fisiología , Neuropatía Hereditaria Motora y Sensorial/metabolismo , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Proteínas de la Mielina/metabolismo , Retina/diagnóstico por imagen , Eliminación de Secuencia , Tomografía de Coherencia Óptica , Agudeza Visual/fisiología , Corteza Visual/diagnóstico por imagen , Corteza Visual/fisiología , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/fisiologíaRESUMEN
Schwann cells in the peripheral nervous systems extend their membranes to wrap axons concentrically and form the insulating sheath, called myelin. The spaces between layers of myelin are sealed by myelin junctions. This tight insulation enables rapid conduction of electric impulses (action potentials) through axons. Demyelination (stripping off the insulating sheath) has been widely regarded as one of the most important mechanisms altering the action potential propagation in many neurological diseases. However, the effective nerve conduction is also thought to require a proper myelin seal through myelin junctions such as tight junctions and adherens junctions. In the present study, we have demonstrated the disruption of myelin junctions in a mouse model (Pmp22+/-) of hereditary neuropathy with liability to pressure palsies (HNPP) with heterozygous deletion of Pmp22 gene. We observed a robust increase of F-actin in Pmp22+/- nerve regions where myelin junctions were disrupted, leading to increased myelin permeability. These abnormalities were present long before segmental demyelination at the late phase of Pmp22+/- mice. Moreover, the increase of F-actin levels correlated with an enhanced activity of p21-activated kinase (PAK1), a molecule known to regulate actin polymerization. Pharmacological inhibition of PAK normalized levels of F-actin, and completely prevented the progression of the myelin junction disruption and nerve conduction failure in Pmp22+/- mice. Our findings explain how abnormal myelin permeability is caused in HNPP, leading to impaired action potential propagation in the absence of demyelination. We call it "functional demyelination", a novel mechanism upstream to the actual stripping of myelin that is relevant to many demyelinating diseases. This observation also provides a potential therapeutic approach for HNPP.
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Artrogriposis/metabolismo , Neuropatía Hereditaria Motora y Sensorial/metabolismo , Uniones Intercelulares/metabolismo , Vaina de Mielina/metabolismo , Quinasas p21 Activadas/metabolismo , Actinas/metabolismo , Potenciales de Acción , Animales , Artrogriposis/genética , Células Cultivadas , Eliminación de Gen , Neuropatía Hereditaria Motora y Sensorial/genética , Heterocigoto , Ratones , Ratones Endogámicos C57BL , Proteínas de la Mielina/genética , Vaina de Mielina/patología , Vaina de Mielina/fisiología , Inhibidores de Proteínas Quinasas/farmacología , Quinasas p21 Activadas/antagonistas & inhibidoresRESUMEN
Goldberg-Shprintzen megacolon syndrome (GOSHS) (OMIM 609460) is characterized by a combination of learning difficulties, characteristic dysmorphic features and Hirschsprung's disease. Variable clinical features include iris coloboma, congenital heart defects and central nervous system abnormalities, in particular polymicrogyria. GOSHS has been attributed to recessive mutations in KIAA1279, encoding kinesin family member (KIF)-binding protein (KBP) with a crucial role in neuronal microtubule dynamics. Here we report on a 7-year-old girl with GOSHS as a result of a homozygous deletion of exons 5 and 6 of the KIAA1279 gene. She had been referred with the suspicion of an underlying neuromuscular disorder before the genetic diagnosis was established, prompted by the findings of motor developmental delay, hypotonia, ptosis and absent reflexes. Neurophysiological studies revealed unequivocal evidence of a peripheral axonal sensory motor neuropathy. We hypothesize that an axonal sensory motor neuropathy may be part of the phenotypical spectrum of KIAA1279-related GOSHS, probably reflecting the effects of reduced KBP protein expression on peripheral neuronal function.
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Secuencia de Bases , Anomalías Craneofaciales/genética , Neuropatía Hereditaria Motora y Sensorial/genética , Enfermedad de Hirschsprung/genética , Proteínas del Tejido Nervioso/genética , Eliminación de Secuencia , Niño , Anomalías Craneofaciales/metabolismo , Anomalías Craneofaciales/patología , Exones , Femenino , Expresión Génica , Neuropatía Hereditaria Motora y Sensorial/metabolismo , Neuropatía Hereditaria Motora y Sensorial/patología , Enfermedad de Hirschsprung/metabolismo , Enfermedad de Hirschsprung/patología , Humanos , Datos de Secuencia Molecular , Proteínas del Tejido Nervioso/deficiencia , Células Receptoras Sensoriales/metabolismo , Células Receptoras Sensoriales/patologíaRESUMEN
Peripheral nerves have peculiar energetic requirements because of considerable length of axons and therefore correct mitochondria functioning and distribution along nerves is fundamental. Mitochondrial dynamics refers to the continuous change in size, shape, and position of mitochondria within cells. Abnormalities of mitochondrial dynamics produced by mutations in proteins involved in mitochondrial fusion (mitofusin-2, MFN2), fission (ganglioside-induced differentiation-associated protein-1, GDAP1), and mitochondrial axonal transport usually present with a Charcot-Marie-Tooth disease (CMT) phenotype. MFN2 mutations cause CMT type 2A by altering mitochondrial fusion and trafficking along the axonal microtubule system. CMT2A is an axonal autosomal dominant CMT type which in most cases is characterized by early onset and rather severe course. GDAP1 mutations also alter fission, fusion and transport of mitochondria and are associated either with recessive demyelinating (CMT4A) and axonal CMT (AR-CMT2K) and, less commonly, with dominant, milder, axonal CMT (CMT2K). OPA1 (Optic Atrophy-1) is involved in fusion of mitochondrial inner membrane, and its heterozygous mutations lead to early-onset and progressive dominant optic atrophy which may be complicated by other neurological symptoms including peripheral neuropathy. Mutations in several proteins fundamental for the axonal transport or forming the axonal cytoskeleton result in peripheral neuropathy, i.e., CMT, distal hereditary motor neuropathy (dHMN) or hereditary sensory and autonomic neuropathy (HSAN), as well as in hereditary spastic paraplegia. Indeed, mitochondrial transport involves directly or indirectly components of the kinesin superfamily (KIF5A, KIF1A, KIF1B), responsible of anterograde transport, and of the dynein complex and related proteins (DYNC1H1, dynactin, dynamin-2), implicated in retrograde flow. Microtubules, neurofilaments, and chaperones such as heat shock proteins (HSPs) also have a fundamental role in mitochondrial transport and mutations in some of related encoding genes cause peripheral neuropathy (TUBB3, NEFL, HSPB1, HSPB8, HSPB3, DNAJB2). In this review, we address the abnormalities in mitochondrial dynamics and their role in determining CMT disease and related neuropathies.
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Neuropatía Hereditaria Motora y Sensorial/metabolismo , Dinámicas Mitocondriales , Transporte Axonal , Enfermedad de Charcot-Marie-Tooth/clasificación , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/metabolismo , Neuropatía Hereditaria Motora y Sensorial/clasificación , Neuropatía Hereditaria Motora y Sensorial/genética , Humanos , Mitocondrias/genética , Mitocondrias/metabolismo , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , MutaciónRESUMEN
Late-onset painful sensory neuropathies are usually acquired conditions associated with common diseases. Adult presentations of known hereditary forms are often accompanied by other organ involvement. We recruited a large French-Canadian family with a dominantly inherited late-onset painful sensory neuropathy. The main clinical feature is recurrent leg pain that progresses to constant painful paraesthesias in the feet and later the hands. As it evolves, some patients develop a mild sensory ataxia. We selected four affected individuals for whole exome sequencing. Analysis of rare variants shared by all cases led to a list of four candidate variants. Segregation analysis in all 45 recruited individuals has shown that only the p.Ile403Thr variant in the α-N-acetyl-glucosaminidase (NAGLU) gene segregates with the disease. Recessive NAGLU mutations cause the severe childhood lysosomal disease mucopolysacharidosis IIIB. Family members carrying the mutation showed a significant decrease of the enzymatic function (average 45%). The late-onset and variable severity of the symptoms may have precluded the description of such symptoms in parents of mucopolysaccharidosis IIIB cases. The identification of a dominant phenotype associated with a NAGLU mutation supports that some carriers of lysosomal enzyme mutations may develop later in life much milder phenotypes.
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Acetilglucosaminidasa/genética , Genes Dominantes/genética , Predisposición Genética a la Enfermedad/genética , Neuropatía Hereditaria Motora y Sensorial/genética , Mutación/genética , Dolor/genética , Enfermedades del Sistema Nervioso Periférico/genética , Acetilglucosaminidasa/metabolismo , Adulto , Anciano , Femenino , Neuropatía Hereditaria Motora y Sensorial/complicaciones , Neuropatía Hereditaria Motora y Sensorial/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Dolor/complicaciones , Dolor/metabolismo , Linaje , Enfermedades del Sistema Nervioso Periférico/complicaciones , Enfermedades del Sistema Nervioso Periférico/metabolismo , Adulto JovenRESUMEN
Mutations in ATP7A lead to at least three allelic disorders: Menkes disease (MD), Occipital horn syndrome and X-linked distal motor neuropathy. These disorders are mainly seen in male individuals, but a few affected females have been described. More than 400 different mutations have been identified in the ATP7A gene. We have conducted several studies in the hope of uncovering the relationship between genotype and phenotype. We have examined the X-inactivation pattern in affected females, the effect of exon-deletions and--duplications, and splice-site mutations on the composition and amount of ATP7A transcript, and we have examined the structural location of missense mutations. The X-inactivation pattern did not fully explain the manifestation of MD in a small fraction of carriers. Most of the affected females had preferential inactivation of the X-chromosome with the normal ATP7A gene, but a few individuals exhibited preferential inactivation of the X-chromosome with the mutated ATP7A gene. The observed mild phenotype in some patients with mutations that effect the composition of the ATP7A transcript, seems to be explained by the presence of a small amount of normal ATP7A transcript. The location of missense mutations on structural models of the ATP7A protein suggests that affected conserved residues generally lead to a severe phenotype. The ATP7A protein traffics within the cells. At low copper levels, ATP7A locates to the Trans-Golgi Network (TGN) to load cuproenzymes with copper, whereas at higher concentrations, ATP7A shifts to the post-Golgi compartments or to the plasma membrane to export copper out of the cell. Impaired copper-regulation trafficking has been observed for ATP7A mutants, but its impact on the clinical outcome is not clear. The major problem in patients with MD seems to be insufficient amounts of copper in the brain. In fact, prenatal treatment of mottled mice as a model for human MD with a combination of chelator and copper, produces a slight increase in copper levels in the brain which perhaps leads to longer survival and more active behavior. In conclusion, small amounts of copper at the right location seem to relieve the symptoms.
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Adenosina Trifosfatasas/metabolismo , Proteínas de Transporte de Catión/metabolismo , Cobre/metabolismo , Cutis Laxo/metabolismo , Síndrome de Ehlers-Danlos/metabolismo , Enfermedades Genéticas Ligadas al Cromosoma X/metabolismo , Neuropatía Hereditaria Motora y Sensorial/metabolismo , Síndrome del Pelo Ensortijado/metabolismo , Mutación , Adenosina Trifosfatasas/genética , Animales , Encéfalo/metabolismo , Proteínas de Transporte de Catión/genética , Quelantes/uso terapéutico , Cobre/deficiencia , Cobre/uso terapéutico , ATPasas Transportadoras de Cobre , Cutis Laxo/genética , Cutis Laxo/fisiopatología , Cutis Laxo/terapia , Enfermedades Carenciales/dietoterapia , Enfermedades Carenciales/etiología , Suplementos Dietéticos , Regulación hacia Abajo , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/fisiopatología , Síndrome de Ehlers-Danlos/terapia , Femenino , Estudios de Asociación Genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/fisiopatología , Enfermedades Genéticas Ligadas al Cromosoma X/terapia , Neuropatía Hereditaria Motora y Sensorial/genética , Neuropatía Hereditaria Motora y Sensorial/fisiopatología , Neuropatía Hereditaria Motora y Sensorial/terapia , Humanos , Masculino , Síndrome del Pelo Ensortijado/genética , Síndrome del Pelo Ensortijado/fisiopatología , Síndrome del Pelo Ensortijado/terapia , Neuronas/metabolismo , Índice de Severidad de la Enfermedad , Inactivación del Cromosoma XRESUMEN
The endolysosomal system and autophagy are essential components of macromolecular turnover in eukaryotic cells. The low-abundance signaling lipid PI(3,5)P2 is a key regulator of this pathway. Analysis of mouse models with defects in PI(3,5)P2 biosynthesis has revealed the unique dependence of the mammalian nervous system on this signaling pathway. This insight led to the discovery of the molecular basis for several human neurological disorders, including Charcot-Marie-Tooth disease and Yunis-Varon syndrome. Spontaneous mutants, conditional knockouts, transgenic lines, and gene-trap alleles of Fig4, Vac14, and Pikfyve (Fab1) in the mouse have provided novel information regarding the role of PI(3,5)P2in vivo. This review summarizes what has been learned from mouse models and highlights the utility of manipulating complex signaling pathways in vivo.
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Flavoproteínas/genética , Neuropatía Hereditaria Motora y Sensorial/genética , Fosfatidilinositol 3-Quinasas/genética , Fosfatos de Fosfatidilinositol/deficiencia , Proteínas Tirosina Fosfatasas no Receptoras/genética , Alelos , Animales , Astrocitos/metabolismo , Astrocitos/patología , Modelos Animales de Enfermedad , Femenino , Flavoproteínas/metabolismo , Técnicas de Inactivación de Genes , Neuropatía Hereditaria Motora y Sensorial/metabolismo , Neuropatía Hereditaria Motora y Sensorial/patología , Heterocigoto , Homocigoto , Humanos , Masculino , Ratones , Ratones Transgénicos , Neuronas/metabolismo , Neuronas/patología , Fosfatidilinositol 3-Quinasas/deficiencia , Fosfoinosítido Fosfatasas , Proteínas Tirosina Fosfatasas no Receptoras/deficienciaRESUMEN
OBJECTIVE: The peripheral myelin protein-22 (PMP22) gene is associated with the most common types of inherited neuropathies, including hereditary neuropathy with liability to pressure palsies (HNPP) caused by PMP22 deficiency. However, the function of PMP22 has yet to be defined. Our previous study has shown that PMP22 deficiency causes an impaired propagation of nerve action potentials in the absence of demyelination. In the present study, we tested an alternative mechanism relating to myelin permeability. METHODS: Utilizing Pmp22(+) (/) (-) mice as a model of HNPP, we evaluated myelin junctions and their permeability using morphological, electrophysiological, and biochemical approaches. RESULTS: We show disruption of multiple types of cell junction complexes in peripheral nerve, resulting in increased permeability of myelin and impaired action potential propagation. We further demonstrate that PMP22 interacts with immunoglobulin domain-containing proteins known to regulate tight/adherens junctions and/or transmembrane adhesions, including junctional adhesion molecule-C (JAM-C) and myelin-associated glycoprotein (MAG). Deletion of Jam-c or Mag in mice recapitulates pathology in HNPP. INTERPRETATION: Our study reveals a novel mechanism by which PMP22 deficiency affects nerve conduction not through removal of myelin, but through disruption of myelin junctions.