RESUMO
Mitofusin-2 (MFN2) is a mitochondrial outer-membrane protein that plays a pivotal role in mitochondrial dynamics in most tissues, yet mutations in MFN2, which cause Charcot-Marie-Tooth disease type 2A (CMT2A), primarily affect the nervous system. We generated a transgenic mouse model of CMT2A that developed severe early onset vision loss and neurological deficits, axonal degeneration without cell body loss, and cytoplasmic and axonal accumulations of fragmented mitochondria. While mitochondrial aggregates were labeled for mitophagy, mutant MFN2 did not inhibit Parkin-mediated degradation, but instead had a dominant negative effect on mitochondrial fusion only when MFN1 was at low levels, as occurs in neurons. Finally, using a transgenic approach, we found that augmenting the level of MFN1 in the nervous system in vivo rescued all phenotypes in mutant MFN2R94Q-expressing mice. These data demonstrate that the MFN1/MFN2 ratio is a key determinant of tissue specificity in CMT2A and indicate that augmentation of MFN1 in the nervous system is a viable therapeutic strategy for the disease.
Assuntos
Axônios/metabolismo , Doença de Charcot-Marie-Tooth/metabolismo , GTP Fosfo-Hidrolases/metabolismo , Animais , Axônios/patologia , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/patologia , Doença de Charcot-Marie-Tooth/prevenção & controle , Modelos Animais de Doenças , GTP Fosfo-Hidrolases/genética , Camundongos , Camundongos Transgênicos , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder. Recent advancements in molecular biology have elucidated the molecular bases of this genetically heterogeneous neuropathy. Still, the major challenge lies in determining the individual contributions by malfunctions of proteins to the disease's pathology. This paper reviews the identified molecular mechanisms underlying major forms of CMT disease. A growing body of evidence has highlighted the role of protein misfolding in demyelinating peripheral neuropathies and neurodegenerative diseases. Several hypotheses have been proposed to explain how misfolded aggregates induce neuronal damage. Current research focuses on developing novel therapeutic targets which aim to prevent, or even reverse the formation of protein aggregation. Interestingly, the role of the cellular defence mechanisms against accumulation of misfolded proteins may play a key role leading to novel strategies for treatment accelerating the clearance of their toxic early aggregates. Based on these findings we propose a model for describing in terms of a formal computer language, the biomolecular processes involving proteins associated with CMT disease.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/prevenção & controle , Modelos Genéticos , Proteínas/genética , Doenças Desmielinizantes/genética , Doenças Desmielinizantes/prevenção & controle , Expressão Gênica , Humanos , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/prevenção & controle , Dobramento de Proteína , Proteínas/química , Transdução de Sinais/genéticaRESUMO
Additional documentation of regional anesthesia in patients with Charcot-Marie-Tooth disease (CMT) is needed to guide practitioners and patients in exploring appropriate options for anesthesia and analgesia management. This case report describes the successful use of a combined spinal-epidural technique for labor progressing to cesarean delivery in a patient with CMT. Previous similar case reports were reviewed and an extensive literature search was conducted to organize the limited body of research regarding use of regional anesthesia in patients with CMT. Opinions regarding regional anesthesia in patients with neuromuscular diseases such as CMT are often contradictory and based on theory rather than documented practice. This case report confirms what seems to be the developing consensus in anesthesia that regional management is a safe alternative to general anesthesia in these patients. Considering that CMT is among the most common of hereditary neuromuscular diseases, it seems valid to establish a more research-driven recommendation for practice.
Assuntos
Anestesia Epidural/métodos , Anestesia Obstétrica/métodos , Raquianestesia/métodos , Doença de Charcot-Marie-Tooth/prevenção & controle , Dor do Parto/tratamento farmacológico , Complicações na Gravidez/prevenção & controle , Adulto , Anestesia Epidural/enfermagem , Anestesia Obstétrica/enfermagem , Raquianestesia/enfermagem , Cesárea , Prática Clínica Baseada em Evidências , Feminino , Humanos , Enfermeiros Anestesistas , Seleção de Pacientes , Gravidez , Resultado da GravidezRESUMO
La enfermedad de Charcot-Marie-Tooth(CMT) es una neuropatía periférica hereditaria que resulta en atrofia muscular y pérdida de la propiocepción en las áreas afectadas. Existe controversia en cuanto a la técnica anestésica ideal a utilizarse en esta enfermedad. La situación basal de los pacientes, la urgencia quirúrgica y los riesgos asociados con las diferentes técnicas anestésicas deben ser tomados en consideración al momento de decidir la técnica a utilizar. Esta descripción de un caso clínico y posterior revisión bibliográfica tiene por objetivo orientar al anestesiólogo en el manejo de la paciente embarazada portadora de la enfermedad de CMT.