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2.
Biochim Biophys Acta Proteins Proteom ; 1868(4): 140363, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31954927

RESUMO

Neuroserpin (NS) is predominantly expressed in brain and inhibits tissue-type plasminogen activator (tPA) with implications in brain development and memory. Nature of conformational change in pathological variants in strand 6B and helix B of NS that cause a relatively mild to severe epilepsy (and/or dementia) remains largely elusive. MD simulation with wild type (WT) NS, strand 6B and helix B variants indicated that substitution in this region affects the conformation of the strands 5B, 5A and reactive centre loop. Therefore, we designed variants of NS in strand 6B (I46D and F48S) and helix B (A54F, L55A and L55P) to investigate their role in tPA inhibition mechanism and propensity to aggregate. An interaction analysis showed disturbance of a hydrophobic patch centered at strands 5B, 6B and helix B in I46D and F48S but not in A54F, L55A, L55P and WT NS. Purified I46D, F48S and L55P variants showed decrease in fluorescence emission intensity but have similar α-helical content, however results of A54F and L55A were comparable to WT NS. Analysis of tPA inhibition showed marginal effect on A54F and L55A variant with tPA-NS complex formation. In contrast, I46D, F48S and L55P variants showed massive decrease in tPA inhibition, with no tPA-NS complex formation. Analysis of native PAGE under under polymerization condition showed prompt conversion of I46D, F48S and L55P to latent conformation but not A54F and L55A variants. Identification of these novel conformational changes will aid in the understanding of variable clinical phenotype of shutter region NS variants and other serpins.


Assuntos
Neuropeptídeos/química , Serpinas/química , Epilepsias Mioclônicas/genética , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Humanos , Interações Hidrofóbicas e Hidrofílicas , Simulação de Dinâmica Molecular , Mutação , Neuropeptídeos/genética , Neuropeptídeos/isolamento & purificação , Neuropeptídeos/metabolismo , Fenótipo , Polimerização , Agregados Proteicos , Conformação Proteica , Conformação Proteica em alfa-Hélice , Serpinas/genética , Serpinas/isolamento & purificação , Serpinas/metabolismo , Ativador de Plasminogênio Tecidual/antagonistas & inibidores
3.
Brain ; 143(1): 94-111, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31855247

RESUMO

Cerebral choline metabolism is crucial for normal brain function, and its homoeostasis depends on carrier-mediated transport. Here, we report on four individuals from three families with neurodegenerative disease and homozygous frameshift mutations (Asp517Metfs*19, Ser126Metfs*8, and Lys90Metfs*18) in the SLC44A1 gene encoding choline transporter-like protein 1. Clinical features included progressive ataxia, tremor, cognitive decline, dysphagia, optic atrophy, dysarthria, as well as urinary and bowel incontinence. Brain MRI demonstrated cerebellar atrophy and leukoencephalopathy. Moreover, low signal intensity in globus pallidus with hyperintensive streaking and low signal intensity in substantia nigra were seen in two individuals. The Asp517Metfs*19 and Ser126Metfs*8 fibroblasts were structurally and functionally indistinguishable. The most prominent ultrastructural changes of the mutant fibroblasts were reduced presence of free ribosomes, the appearance of elongated endoplasmic reticulum and strikingly increased number of mitochondria and small vesicles. When chronically treated with choline, those characteristics disappeared and mutant ultrastructure resembled healthy control cells. Functional analysis revealed diminished choline transport yet the membrane phosphatidylcholine content remained unchanged. As part of the mechanism to preserve choline and phosphatidylcholine, choline transporter deficiency was implicated in impaired membrane homeostasis of other phospholipids. Choline treatments could restore the membrane lipids, repair cellular organelles and protect mutant cells from acute iron overload. In conclusion, we describe a novel childhood-onset neurometabolic disease caused by choline transporter deficiency with autosomal recessive inheritance.


Assuntos
Antígenos CD/genética , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Adolescente , Ataxia/genética , Ataxia/fisiopatologia , Atrofia , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Colina/farmacologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/fisiopatologia , Vesículas Citoplasmáticas/efeitos dos fármacos , Vesículas Citoplasmáticas/ultraestrutura , Transtornos de Deglutição/genética , Transtornos de Deglutição/fisiopatologia , Disartria/genética , Disartria/fisiopatologia , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/ultraestrutura , Incontinência Fecal/genética , Incontinência Fecal/fisiopatologia , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/ultraestrutura , Mutação da Fase de Leitura , Globo Pálido/diagnóstico por imagem , Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico por imagem , Transtornos Heredodegenerativos do Sistema Nervoso/patologia , Transtornos Heredodegenerativos do Sistema Nervoso/fisiopatologia , Homozigoto , Humanos , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Leucoencefalopatias/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Microscopia Eletrônica , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Nootrópicos/farmacologia , Atrofia Óptica/genética , Atrofia Óptica/fisiopatologia , Linhagem , Ribossomos/efeitos dos fármacos , Ribossomos/ultraestrutura , Substância Negra/diagnóstico por imagem , Síndrome , Tremor/genética , Tremor/fisiopatologia , Incontinência Urinária/genética , Incontinência Urinária/fisiopatologia
4.
Mol Cell ; 75(5): 1073-1085.e6, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31327635

RESUMO

Mitochondrial AAA+ quality-control proteases regulate diverse aspects of mitochondrial biology through specialized protein degradation, but the underlying mechanisms of these enzymes remain poorly defined. The mitochondrial AAA+ protease AFG3L2 is of particular interest, as genetic mutations localized throughout AFG3L2 are linked to diverse neurodegenerative disorders. However, a lack of structural data has limited our understanding of how mutations impact enzymatic function. Here, we used cryoelectron microscopy (cryo-EM) to determine a substrate-bound structure of the catalytic core of human AFG3L2. This structure identifies multiple specialized structural features that integrate with conserved motifs required for ATP-dependent translocation to unfold and degrade targeted proteins. Many disease-relevant mutations localize to these unique structural features of AFG3L2 and distinctly influence its activity and stability. Our results provide a molecular basis for neurological phenotypes associated with different AFG3L2 mutations and establish a structural framework to understand how different members of the AAA+ superfamily achieve specialized biological functions.


Assuntos
Proteases Dependentes de ATP/química , ATPases Associadas a Diversas Atividades Celulares/química , Proteínas Mitocondriais/química , Mutação , Proteases Dependentes de ATP/genética , Proteases Dependentes de ATP/metabolismo , ATPases Associadas a Diversas Atividades Celulares/genética , ATPases Associadas a Diversas Atividades Celulares/metabolismo , Microscopia Crioeletrônica , Células HEK293 , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Transtornos Heredodegenerativos do Sistema Nervoso/metabolismo , Humanos , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Domínios Proteicos
5.
Int Rev Neurobiol ; 145: 127-176, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31208522

RESUMO

Peripheral neuropathy is a common and debilitating complication of diabetes and prediabetes. Recent clinical studies have identified an association between the development of neuropathy and dyslipidemia in prediabetic and diabetic patients. Despite the prevalence of this complication, studies identifying molecular mechanisms that underlie neuropathy progression in prediabetes or diabetes are limited. However, dysfunctional mitochondrial pathways in hereditary neuropathy provide feasible molecular targets for assessing mitochondrial dysfunction in neuropathy associated with prediabetes or diabetes. Recent studies suggest that elevated levels of dietary saturated fatty acids (SFAs) associated with dyslipidemia impair mitochondrial dynamics in sensory neurons by inducing mitochondrial depolarization, compromising mitochondrial bioenergetics, and impairing axonal mitochondrial transport. This causes lower neuronal ATP and apoptosis. Conversely, monounsaturated fatty acids (MUFAs) restore nerve and sensory mitochondrial function. Understanding the mitochondrial pathways that contribute to neuropathy progression in prediabetes and diabetes may provide therapeutic targets for the treatment of this debilitating complication.


Assuntos
Complicações do Diabetes/fisiopatologia , Diabetes Mellitus/fisiopatologia , Transtornos Heredodegenerativos do Sistema Nervoso/fisiopatologia , Dinâmica Mitocondrial/fisiologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Animais , Dislipidemias/complicações , Dislipidemias/fisiopatologia , Gânglios Espinais/metabolismo , Transtornos Heredodegenerativos do Sistema Nervoso/complicações , Humanos , Hiperglicemia/complicações , Hiperglicemia/fisiopatologia , Doenças do Sistema Nervoso Periférico/complicações
6.
Neurología (Barc., Ed. impr.) ; 34(5): 283-290, jun. 2019. tab
Artigo em Espanhol | IBECS | ID: ibc-180844

RESUMO

Introducción: El cáncer y las enfermedades degenerativas constituyen trastornos con algunos mecanismos compartidos que actúan en sentido opuesto, produciendo un fenómeno incontrolado de proliferación o pérdida de células. Observaciones diversas apuntan que los pacientes con enfermedad de Alzheimer tienen menor riesgo de desarrollar tumores y viceversa. En este artículo se expone la prevalencia de tumores (activos o superados) en pacientes de neurología cognitiva con y sin una enfermedad degenerativa demenciante. Pacientes y método: En 1.164 pacientes se analizó la frecuencia y topografía de tumores y la presencia o ausencia de enfermedad neurodegenerativa, que se clasificó en 4 grupos (enfermedad de Alzheimer, sinucleinopatía, enfermedad del complejo Pick y del complejo de poliglutamina). Se comparó la frecuencia de tumor en los subgrupos con y sin enfermedad degenerativa, y de esta en los pacientes con y sin trastorno tumoral. Resultados: Se registró proceso tumoral en el 12,1% de los pacientes con enfermedad neurodegenerativa y en el 17,3% del resto del grupo. En el grupo del estudio, un 14,8% de los que tienen antecedente tumoral fue diagnosticado de enfermedad neurodegenerativa, frente al 20,8% entre los que no tienen ese antecedente. Estas diferencias y las observadas en la comparación de subgrupos (tipo de enfermedad degenerativa y topografía del tumor) no alcanzaron significación estadística, excepto al contrastar enfermedades neurodegenerativas con tumores del sistema nervioso central y sinucleinopatías con neoplasias. Conclusiones: Las enfermedades neoplásicas y las neurodegenerativas demenciantes no son excluyentes, aunque muestran menor asociación de la esperada por su respectiva prevalencia


Background: Cancer and degenerative diseases share some pathogenic mechanisms which act in opposition to one another to produce either uncontrolled cell proliferation or cell death. According to several studies, patients with Alzheimer disease have a lower risk of neoplasia, and vice versa. This study describes the prevalence of tumours (active or successfully treated) in a series of patients with and without a dementing degenerative disease treated at a cognitive neurology unit. Patients and method: We analysed the frequency and topography of tumours and the presence or absence of a neurodegenerative disease in a group of 1,164 patients. Neurodegenerative diseases were classified in 4 groups: Alzheimer disease, synucleinopathies, Pick complex, and polyglutamine complex. We subsequently compared tumour frequency in patients with and without a degenerative disease, and prevalence of neurodegenerative diseases in patients with and without tumours. Results: Tumours were detected in 12.1% of the patients with a neurodegenerative disease and in 17.3% of the remaining patients. Around 14.8% of the patients with a history of neoplasia and 20.8% of the patients with no history of neoplasia were diagnosed with a neurodegenerative disease. Except for these differences and the differences between subgroups (type of degenerative disease and tumour location) were not statistically significant, except when comparing neurodegenerative diseases to central nervous system tumours, and synucleinopathies to neoplasms. Conclusion: Dementing degenerative diseases and neoplastic disorders are not mutually exclusive. Nevertheless, the rate of co-occurrence is lower than would be expected given the prevalence rate for each group


Assuntos
Humanos , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Doenças Neurodegenerativas/complicações , Doença de Alzheimer/complicações , Fatores de Proteção , Doença de Pick/complicações , Sinucleínas/fisiologia , Fatores de Risco , Transtornos Heredodegenerativos do Sistema Nervoso/complicações , Estudos Retrospectivos
7.
Brain ; 142(6): 1561-1572, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31135052

RESUMO

The endoplasmic reticulum enzyme fatty acid 2-hydroxylase (FA2H) plays a major role in the formation of 2-hydroxy glycosphingolipids, main components of myelin. FA2H deficiency in mice leads to severe central demyelination and axon loss. In humans it has been associated with phenotypes from the neurodegeneration with brain iron accumulation (fatty acid hydroxylase-associated neurodegeneration, FAHN), hereditary spastic paraplegia (HSP type SPG35) and leukodystrophy (leukodystrophy with spasticity and dystonia) spectrum. We performed an in-depth clinical and retrospective neurophysiological and imaging study in a cohort of 19 cases with biallelic FA2H mutations. FAHN/SPG35 manifests with early childhood onset predominantly lower limb spastic tetraparesis and truncal instability, dysarthria, dysphagia, cerebellar ataxia, and cognitive deficits, often accompanied by exotropia and movement disorders. The disease is rapidly progressive with loss of ambulation after a median of 7 years after disease onset and demonstrates little interindividual variability. The hair of FAHN/SPG35 patients shows a bristle-like appearance; scanning electron microscopy of patient hair shafts reveals deformities (longitudinal grooves) as well as plaque-like adhesions to the hair, likely caused by an abnormal sebum composition also described in a mouse model of FA2H deficiency. Characteristic imaging features of FAHN/SPG35 can be summarized by the 'WHAT' acronym: white matter changes, hypointensity of the globus pallidus, ponto-cerebellar atrophy, and thin corpus callosum. At least three of four imaging features are present in 85% of FA2H mutation carriers. Here, we report the first systematic, large cohort study in FAHN/SPG35 and determine the phenotypic spectrum, define the disease course and identify clinical and imaging biomarkers.


Assuntos
Transtornos Heredodegenerativos do Sistema Nervoso/genética , Fenótipo , Paraplegia Espástica Hereditária/genética , Criança , Estudos de Coortes , Doenças Desmielinizantes/genética , Feminino , Humanos , Masculino , Oxigenases de Função Mista/genética , Mutação/genética , Linhagem , Estudos Retrospectivos , Paraplegia Espástica Hereditária/classificação
8.
Oxid Med Cell Longev ; 2019: 6392763, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31057691

RESUMO

The mitochondrion is an essential organelle important for the generation of ATP for cellular function. This is especially critical for cells with high energy demands, such as neurons for signal transmission and cardiomyocytes for the continuous mechanical work of the heart. However, deleterious reactive oxygen species are generated as a result of mitochondrial electron transport, requiring a rigorous activation of antioxidative defense in order to maintain homeostatic mitochondrial function. Indeed, recent studies have demonstrated that the dysregulation of antioxidant response leads to mitochondrial dysfunction in human degenerative diseases affecting the nervous system and the heart. In this review, we outline and discuss the mitochondrial and oxidative stress factors causing degenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and Friedreich's ataxia. In particular, the pathological involvement of mitochondrial dysfunction in relation to oxidative stress, energy metabolism, mitochondrial dynamics, and cell death will be explored. Understanding the pathology and the development of these diseases has highlighted novel regulators in the homeostatic maintenance of mitochondria. Importantly, this offers potential therapeutic targets in the development of future treatments for these degenerative diseases.


Assuntos
Antioxidantes/metabolismo , Apoptose , Autofagia , Metabolismo Energético , Transtornos Heredodegenerativos do Sistema Nervoso/metabolismo , Mitocôndrias/metabolismo , Estresse Oxidativo , Transtornos Heredodegenerativos do Sistema Nervoso/patologia , Humanos , Mitocôndrias/patologia , Neurônios/metabolismo , Neurônios/patologia , Espécies Reativas de Oxigênio/metabolismo
9.
Acta Med Port ; 32(4): 295-304, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31067424

RESUMO

INTRODUCTION: The national protocol of genetic counselling and pre-symptomatic testing for late-onset neurological diseases began in Portugal in 1995. Initially, it was accessible only to adults at-risk for Machado-Joseph disease, but was later extended to other hereditary ataxias, to Huntington's disease and to familial amyloid polyneuropathy caused by Val30Met mutation at the transthyretin gene. The aim of this study was to describe the profile of the population seeking pre-symptomatic testing, while also reflecting on the experience of conducting the protocol of multidisciplinary sessions since 1996. MATERIAL AND METHODS: We conducted a retrospective study and collected data from clinical records of consultands who requested pre-symptomatic testing at our centre in Porto (Portugal) during the first twenty years of practice (1996 - 2015). RESULTS: A total of 1446 records were reviewed. The most common reason for testing was to reduce uncertainty (41.7%). The rate of withdrawals before results disclosure was lower (16%) than reported in other international experiences with pre-symptomatic testing, while 45% of the consultands dropped out the protocol after learning the test results (73.5% of them were non-carriers). As far as the mutation carriers were concerned, 29.6% adhered to the protocol a year after test disclosure. Consultands that had learned about presymptomatic testing through healthcare professionals tended to adhere more to pre-symptomatic testing consultations. DISCUSSION: The profile of Portuguese consultands at risk for late-onset neurological diseases is similar to those reported in other international programs. The largest group in this data set was the one comprising the subjects at risk for familial amyloid polyneuropathy caused by Val30Met mutation at the transthyretin gene, and it is likely that therapeutic options for this condition may have influenced this result. Adherence to pre-symptomatic testing may change in the future since effective therapies are available (or given the fact that people think effective treatments are imminent). CONCLUSION: This study reflects the first comprehensive description of a Portuguese experience with pre-symptomatic testing for late onset neurological diseases. The development of innovative approaches to improve the consultands' experience with pre-symptomatic testing and their engagement in genetic departments is still a challenge in Portuguese genetics healthcare departments. A better coordination among primary care and genetics healthcare services is needed.


Assuntos
Doenças Assintomáticas , Aconselhamento Genético/estatística & dados numéricos , Testes Genéticos/estatística & dados numéricos , Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico , Exame Neurológico/estatística & dados numéricos , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/genética , Revelação , Triagem de Portadores Genéticos , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Transtornos Heredodegenerativos do Sistema Nervoso/psicologia , Humanos , Doença de Machado-Joseph/diagnóstico , Doença de Machado-Joseph/genética , Pessoa de Meia-Idade , Exame Neurológico/psicologia , Pacientes Desistentes do Tratamento/estatística & dados numéricos , Portugal , Estudos Retrospectivos , Fatores Socioeconômicos , Fatores de Tempo , Adulto Jovem
10.
JAMA Neurol ; 76(6): 650-656, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30933216

RESUMO

Importance: Nine hereditary neurodegenerative diseases are known as polyglutamine diseases, including Huntington disease, 6 spinocerebellar ataxias (SCAs) (SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17), dentatorubral-pallidoluysion atrophy, and spinal bulbar muscular atrophy. Objective: To determine the prevalence of carriers of intermediate and pathological polyglutamine disease-associated alleles among the general population. Design, Setting, and Participants: This observational cross-sectional study included data from 5 large European population-based cohorts that were compiled between 1997 and 2012, and the analyses were conducted in 2018. In total, 16 547 DNA samples were obtained from participants of the 5 cohorts. Individuals with a lifetime diagnosis of major depression were excluded (n = 2351). In the remaining 14 196 participants without an established polyglutamine disease diagnosis, the CAG repeat size in both alleles of all 9 polyglutamine disease-associated genes (PDAGs) (ie, ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP, HTT, ATN1, and AR) was determined. Exposure: The number of CAG repeats in the alleles of the 9 PDAGs. Main Outcomes and Measures: The number of individuals with alleles within the intermediate or pathological range per PDAG, as well as differences in sex, age, and body mass index between individuals carrying alleles within the normal or intermediate range and individuals carrying alleles within the pathological range of PDAGs. Results: In the 14 196 analyzed participants (age range, 18-99 years; 56.3% female), 10.7% had a CAG repeat number within the intermediate range of at least 1 PDAG. Moreover, up to 1.3% of the participants had a CAG repeat number within the disease-causing range, predominantly in the lower pathological range associated with elderly onset. No differences in sex, age, or body mass index were found between individuals with CAG repeat numbers within the pathological range and individuals with CAG repeat numbers within the normal or intermediate range. Conclusions and Relevance: These results indicate a high prevalence of individuals carrying intermediate and pathological ranges of polyglutamine disease-associated alleles among the general population. Therefore, a substantially larger proportion of individuals than previously estimated may be at risk of developing a polyglutamine disease later in life or bearing children with a de novo mutation.


Assuntos
Transtornos Heredodegenerativos do Sistema Nervoso/genética , Heterozigoto , Peptídeos/genética , Repetições de Trinucleotídeos/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos Transversais , Europa (Continente)/epidemiologia , Feminino , Transtornos Heredodegenerativos do Sistema Nervoso/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Adulto Jovem
12.
Neuroimage Clin ; 21: 101666, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30682531

RESUMO

Huntington's Disease-Like 2 (HDL2), caused by a CTG/CAG expansion in JPH3 on chromosome 16q24, is the most common Huntington's Disease (HD) phenocopy in populations with African ancestry. Qualitatively, brain MRIs of HDL2 patients have been indistinguishable from HD. To determine brain regions most affected in HDL2 a cross-sectional study using MRI brain volumetry was undertaken to compare the brains of nine HDL2, 11 HD and nine age matched control participants. Participants were ascertained from the region in South Africa with the world's highest HDL2 incidence. The HDL2 and HD patient groups showed no significant differences with respect to mean age at MRI, disease duration, abnormal triplet repeat length, or age at disease onset. Overall, intracerebral volumes were smaller in both affected groups compared to the control group. Comparing the HDL2 and HD groups across multiple covariates, cortical and subcortical volumes were similar with the exception that the HDL2 thalamic volumes were smaller. Consistent with other similarities between the two diseases, these results indicate a pattern of neurodegeneration in HDL2 that is remarkably similar to HD. However smaller thalamic volumes in HDL2 raises intriguing questions into the pathogenesis of both disorders, and how these volumetric differences relate to their respective phenotypes.


Assuntos
Encéfalo/patologia , Coreia/patologia , Transtornos Cognitivos/patologia , Demência/patologia , Transtornos Heredodegenerativos do Sistema Nervoso/patologia , Doença de Huntington/patologia , Imagem por Ressonância Magnética , Adulto , Idoso , Tronco Encefálico/patologia , Estudos Transversais , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Expansão das Repetições de Trinucleotídeos/fisiologia
14.
Curr Genet ; 65(1): 17-28, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29974202

RESUMO

Trinucleotide repeats are a particular class of microsatellites whose large expansions are responsible for at least two dozen human neurological and developmental disorders. Slippage of the two complementary DNA strands during replication, homologous recombination or DNA repair is generally accepted as a mechanism leading to repeat length changes, creating expansions and contractions of the repeat tract. The present review focuses on recent developments on double-strand break repair involving trinucleotide repeat tracts. Experimental evidences in model organisms show that gene conversion and break-induced replication may lead to large repeat tract expansions, while frequent contractions occur either by single-strand annealing between repeat ends or by gene conversion, triggering near-complete contraction of the repeat tract. In the second part of this review, different therapeutic approaches using highly specific single- or double-strand endonucleases targeted to trinucleotide repeat loci are compared. Relative efficacies and specificities of these nucleases will be discussed, as well as their potential strengths and weaknesses for possible future gene therapy of these dramatic disorders.


Assuntos
Quebras de DNA de Cadeia Dupla , Reparo do DNA , Terapia Genética/métodos , Repetições de Trinucleotídeos/genética , DNA/genética , DNA/metabolismo , Endonucleases/metabolismo , Terapia Genética/tendências , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Transtornos Heredodegenerativos do Sistema Nervoso/metabolismo , Humanos , Modelos Genéticos , Expansão das Repetições de Trinucleotídeos/genética
15.
Eur J Med Genet ; 62(12): 103594, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30503856

RESUMO

Distal hereditary motor neuropathies (dHMNs) comprise a group of clinically and genetically heterogeneous inherited lower motor neuron syndromes mainly characterized by a distal-predominant pattern of progressive muscle atrophy, weakness and hyporeflexia, without sensory dysfunction. Although at least 21 causative genes for dHMN have been reported, mutational scanning of these genes often fails to identify the causative variants in dHMN cohorts, suggesting that additional causative genes remain to be identified. We studied a four-generation pedigree of a Japanese family with autosomal dominant dHMN to provide insight into the pathogenetic basis of the disease. Neurological examinations were performed on all six family members enrolled in this study. Whole-exome sequencing (WES) was used to identify the causative gene for dHMN. The clinical features of the patients included muscle weakness with distal extensor dominancy in the lower extremities, accompanied by facial and neck flexor muscle impairment, no sensory involvement, and areflexia. Nerve conduction studies demonstrated axonal changes mainly in the peroneal nerve. WES combined with rigorous filtering revealed three missense variants (NM_001083964: c.851G > A [p.Arg284His] in TDRKH, NM_002858: c.1654G > T [p.Gly552Cys] in ABCD3, NM_001005164: c.898A > T [p.Ile300Phe], in OR52E2). The variant in TDRKH is located in a conserved region of the tudor domain which is also present in the survival of motor neuron (SMN) protein, encoded by the SMN1 gene. Therefore, we concluded the variant in TDRKH is likely to be responsible for dHMN in our pedigree.


Assuntos
Transtornos Heredodegenerativos do Sistema Nervoso/genética , Doença dos Neurônios Motores/genética , Proteínas de Ligação a RNA/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Genes Dominantes , Transtornos Heredodegenerativos do Sistema Nervoso/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Doença dos Neurônios Motores/patologia , Músculo Esquelético/fisiopatologia , Mutação de Sentido Incorreto , Linhagem , Nervo Fibular/fisiopatologia , Reflexo
16.
Clin Genet ; 95(1): 182-186, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30298599

RESUMO

MPV17 encodes a putative channel-forming protein of the inner mitochondrial membrane and is involved in mitochondrial deoxynucleotide homeostasis. MPV17 mutations were first reported in patients with Navajo neurohepatopathy, an autosomal recessive mitochondrial DNA depletion syndrome, characterized by early-onset liver failure, failure to thrive as well as central and peripheral neurological involvement. Recently, two patients with juvenile-onset peripheral sensorimotor neuropathy associated with an MVP17 c.122G>A (p.Arg41Gln) variant have been reported. Here, we describe five additional patients from two unrelated families with sensorimotor axonal neuropathy without hepatocerebral affection caused by homozygous MPV17 variants. Patients of the first family carried the known c.122G>A variant and affected individuals of the second family had a novel c.376-9T>G near-splice variant, which was shown to result in an in-frame deletion of 11 amino acids. This report provides further evidence that MPV17 mutations should be considered in patients with pure, non-syndromic axonal neuropathy.


Assuntos
Predisposição Genética para Doença , Proteínas de Membrana/genética , Proteínas Mitocondriais/genética , Doenças do Sistema Nervoso Periférico/genética , Polineuropatias/genética , Adolescente , Adulto , Idade de Início , Axônios/patologia , Criança , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/fisiopatologia , Feminino , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Transtornos Heredodegenerativos do Sistema Nervoso/fisiopatologia , Humanos , Hepatopatias/genética , Hepatopatias/fisiopatologia , Falência Hepática/genética , Falência Hepática/fisiopatologia , Masculino , Doenças Mitocondriais/genética , Doenças Mitocondriais/fisiopatologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Polineuropatias/fisiopatologia , Córtex Sensório-Motor/fisiopatologia , Adulto Jovem
17.
Rev Neurol (Paris) ; 175(4): 238-246, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30293881

RESUMO

Facial-onset sensory and motor neuronopathy (FOSMN) syndrome represents a rare, slowly progressive, lower motor neuron disease with sensory compromise, involving mainly the face, bulbar region and upper limbs. However, non-motor symptoms and neurogenetic studies have rarely been evaluated in large case series. In the present study, 10 unrelated Brazilian patients with FOSMN syndrome underwent extensive clinical, laboratory, neurophysiological and neurogenetic assessment. Median age at symptom onset was 52.1 years, and men and women were equally affected. Patients presented with hemifacial or bilateral facial paresthesia and weakness, which evolved with dysphagia, dysphonia, and facial and tongue atrophy and, finally, a dropped-head, upper limb weakness and syringomyelia-like sensory disturbances in the upper limbs. All 10 patients showed chronic diffuse neurogenic compromise of bulbar, cervical and thoracic myotomes, and abnormal blink reflex tests. A positive family history of neurodegeneration was identified in six cases, and revealed pathogenic gene variants in three families (involving VCP, TARDBP and CHCHD10). Thus, our case series has revealed new findings regarding FOSMN syndrome: (i) its clinical course is not always benign, with poorer prognoses associated with dropped-head syndrome and early bulbar compromise; (ii) FOSMN syndrome may be part of a complex familial neurodegenerative spectrum; and (iii) a definite genetic basis may be observed in some cases.


Assuntos
Doenças do Nervo Facial/fisiopatologia , Doença dos Neurônios Motores/fisiopatologia , Adulto , Idade de Início , Idoso , Piscadela , Brasil , Doenças do Nervo Facial/diagnóstico por imagem , Doenças do Nervo Facial/genética , Feminino , Testes Genéticos , Transtornos Heredodegenerativos do Sistema Nervoso/epidemiologia , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Humanos , Masculino , Pessoa de Meia-Idade , Doença dos Neurônios Motores/diagnóstico por imagem , Doença dos Neurônios Motores/genética , Debilidade Muscular/etiologia , Atrofia Muscular Espinal/epidemiologia , Neuroimagem , Exame Neurológico , Parestesia/etiologia
18.
Chembiochem ; 20(5): 634-643, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30393919

RESUMO

Precise editing of the genome of a living body is a goal pursued by scientists in many fields. In recent years, CRISPR (clustered regularly interspaced short palindromic repeat)/Cas (CRISPR-associated) genome-editing systems have become a revolutionary toolbox for gene editing across various species. However, the low transfection efficiency of the CRISPR/Cas9 system to mammalian cells in vitro and in vivo is a big obstacle hindering wide and deep application. In this review, recently developed delivery strategies for various CRISPR/Cas9 formulations and their applications in treating gene-related diseases are briefly summarized. This review should inspire others to explore more efficient strategies for CRISPR system delivery and gene therapy.


Assuntos
Sistemas CRISPR-Cas/genética , Terapia Genética/métodos , Síndrome de Imunodeficiência Adquirida/terapia , Animais , Sistemas CRISPR-Cas/imunologia , Linhagem Celular , Edição de Genes/métodos , Transtornos Heredodegenerativos do Sistema Nervoso/terapia , Humanos , Terapia de Alvo Molecular , Nanopartículas/uso terapêutico , Neoplasias/terapia
19.
Mol Pharm ; 15(12): 5781-5792, 2018 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-30392378

RESUMO

Polyglutamine diseases are a set of progressive neurodegenerative disorders caused by misfolding and aggregation of mutant CAG RNA and polyglutamin protein. To date, there is a lack of effective therapeutics that can counteract the polyglutamine neurotoxicity. Two peptidylic inhibitors, QBP1 and P3, targeting the protein and RNA toxicities, respectively, have been previously demonstrated by us with combinational therapeutic effects on the Drosophila polyglutamine disease model. However, their therapeutic efficacy has never been investigated in vivo in mammals. The current study aims to (a) develop a brain-targeting delivery system for both QBP1 and L1P3V8 (a lipidated variant of P3 with improved stability) and (b) evaluate their therapeutic effects on the R6/2 transgenic mouse model of polyglutamine disease. Compared with intravenous administration, intranasal administration of QBP1 significantly increased its brain-to-plasma ratio. In addition, employment of a chitosan-containing in situ gel for the intranasal administration of QBP1 notably improved its brain concentration for up to 10-fold. Further study on intranasal cotreatment with the optimized formulation of QBP1 and L1P3V8 in mice found no interference on the brain uptake of each other. Subsequent efficacy evaluation of 4-week daily QBP1 (16 µmol/kg) and L1P3V8 (6 µmol/kg) intranasal cotreatment in the R6/2 mice demonstrated a significant improvement on the motor coordination and explorative behavior of the disease mice, together with a full suppression on the RNA- and protein-toxicity markers in their brains. In summary, the current study developed an efficient intranasal cotreatment of the two peptidylic inhibitors, QBP1 and L1P3V8, for their brain-targeting, and such a novel therapeutic strategy was found to be effective on a transgenic polyglutamine disease mouse model.


Assuntos
Proteínas de Transporte/administração & dosagem , Transtornos Heredodegenerativos do Sistema Nervoso/tratamento farmacológico , Oligopeptídeos/administração & dosagem , Peptídeos/administração & dosagem , Peptídeos/metabolismo , RNA Mensageiro/antagonistas & inibidores , Administração Intranasal , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Proteínas de Transporte/farmacocinética , Modelos Animais de Doenças , Esquema de Medicação , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada/métodos , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Transtornos Heredodegenerativos do Sistema Nervoso/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Oligopeptídeos/farmacocinética , Peptídeos/farmacocinética , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Expansão das Repetições de Trinucleotídeos/genética
20.
Methods Mol Biol ; 1826: 109-121, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30194596

RESUMO

Our current knowledge about the cellular mechanisms underlying serpin-related disorders, the serpinopathies, is predominantly based on studies in cell culture models of disease, particularly for alpha-1 antitrypsin (AAT, SERPINA1) deficiency causing emphysema and the familial encephalopathy with neuroserpin (NS, SERPINI1) inclusion bodies (FENIB). FENIB, a neurodegenerative dementia, is caused by polymerization of NS (Miranda and Lomas, Cell Mol Life Sci 63:709-722, 2006; Roussel BD et al., Epileptic Disor 18:103-110, 2016), while AAT deficiency presents as a result of several divergent mutations in the AAT gene that cause lack of protein synthesis or complete intracellular degradation (null variants) or polymer formation (polymerogenic variants) (Lomas et al., J Hepatol 65:413-424, 2016; Greene et al., Nat Rev Dis Primers 2:16051, 2016; Ferrarotti et al. Orphanet J Rare D 9:172, 2014). Both diseases have been extensively modeled in cell culture systems by expressing mutant variants in a variety of ways. Here we describe the methodologies we follow in our cell model systems used to examine serpin disorders.


Assuntos
Enfisema , Epilepsias Mioclônicas , Transtornos Heredodegenerativos do Sistema Nervoso , Modelos Biológicos , Mutação , Neuropeptídeos , Serpinas , alfa 1-Antitripsina , Animais , Células COS , Chlorocebus aethiops , Enfisema/genética , Enfisema/metabolismo , Enfisema/patologia , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/metabolismo , Epilepsias Mioclônicas/patologia , Células HEK293 , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Transtornos Heredodegenerativos do Sistema Nervoso/metabolismo , Transtornos Heredodegenerativos do Sistema Nervoso/patologia , Humanos , Camundongos , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Células PC12 , Ratos , Serpinas/genética , Serpinas/metabolismo , alfa 1-Antitripsina/genética , alfa 1-Antitripsina/metabolismo
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