Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Mais filtros

Base de dados
Ano de publicação
Tipo de documento
Assunto da revista
Intervalo de ano de publicação
1.
Neurobiol Dis ; 143: 105016, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32653673

RESUMO

The ubiquitin-binding proteasomal shuttle protein UBQLN2 is implicated in common neurodegenerative disorders due to its accumulation in disease-specific aggregates and, when mutated, directly causes familial frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS). Like other proteins linked to FTD/ALS, UBQLN2 undergoes phase separation to form condensates. The relationship of UBQLN2 phase separation and accumulation to neurodegeneration, however, remains uncertain. Employing biochemical, neuropathological and behavioral assays, we studied the impact of overexpressing WT or mutant UBQLN2 in the CNS of transgenic mice. Expression of UBQLN2 harboring a pathogenic mutation (P506T) elicited profound and widespread intraneuronal inclusion formation and aggregation without prominent neurodegenerative or behavioral changes. Both WT and mutant UBQLN2 formed ubiquitin- and P62-positive inclusions in neurons, supporting the view that UBQLN2 is intrinsically prone to phase separate, with the size, shape and frequency of inclusions depending on expression level and the presence or absence of a pathogenic mutation. Overexpression of WT or mutant UBQLN2 resulted in a dose-dependent decrease in levels of a key interacting chaperone, HSP70, as well as dose-dependent profound degeneration of the retina. We conclude that, at least in mice, robust aggregation of a pathogenic form of UBQLN2 is insufficient to cause neuronal loss recapitulating that of human FTD/ALS. Our results nevertheless support the view that altering the normal cellular balance of UBQLN2, whether wild type or mutant protein, has deleterious effects on cells of the CNS and retina that likely reflect perturbations in ubiquitin-dependent protein homeostasis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Relacionadas à Autofagia/metabolismo , Modelos Animais de Doenças , Degeneração Neural/metabolismo , Doenças Neurodegenerativas/metabolismo , Neurônios/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Animais , Proteínas Relacionadas à Autofagia/genética , Demência Frontotemporal/metabolismo , Demência Frontotemporal/patologia , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Degeneração Neural/patologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Neurônios/patologia , Proteostase/fisiologia
2.
Ann Neurol ; 84(1): 64-77, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29908063

RESUMO

OBJECTIVE: Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is the most common dominantly inherited ataxia. Despite advances in understanding this CAG repeat/polyglutamine expansion disease, there are still no therapies to alter its progressive fatal course. Here, we investigate whether an antisense oligonucleotide (ASO) targeting the SCA3 disease gene, ATXN3, can prevent molecular, neuropathological, electrophysiological, and behavioral features of the disease in a mouse model of SCA3. METHODS: The top ATXN3-targeting ASO from an in vivo screen was injected intracerebroventricularly into early symptomatic transgenic SCA3 mice that express the full human disease gene and recapitulate key disease features. Following a single ASO treatment at 8 weeks of age, mice were evaluated longitudinally for ATXN3 suppression and rescue of disease-associated pathological changes. Mice receiving an additional repeat injection at 21 weeks were evaluated longitudinally up to 29 weeks for motor performance. RESULTS: The ATXN3-targeting ASO achieved sustained reduction of polyglutamine-expanded ATXN3 up to 8 weeks after treatment and prevented oligomeric and nuclear accumulation of ATXN3 up to at least 14 weeks after treatment. Longitudinal ASO therapy rescued motor impairment in SCA3 mice, and this rescue was associated with a recovery of defects in Purkinje neuron firing frequency and afterhyperpolarization. INTERPRETATION: This preclinical study established efficacy of ATXN3-targeted ASOs as a disease-modifying therapeutic strategy for SCA3. These results support further efforts to develop ASOs for human clinical trials in this polyglutamine disease as well as in other dominantly inherited disorders caused by toxic gain of function. Ann Neurol 2018;83:64-77.


Assuntos
Ataxina-3/química , Regulação da Expressão Gênica/efeitos dos fármacos , Doença de Machado-Joseph/tratamento farmacológico , Oligonucleotídeos Antissenso/uso terapêutico , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/genética , Fatores Etários , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Ataxina-3/genética , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/genética , Gliose/tratamento farmacológico , Gliose/etiologia , Doença de Machado-Joseph/genética , Doença de Machado-Joseph/patologia , Doença de Machado-Joseph/fisiopatologia , Masculino , Camundongos , Camundongos Transgênicos , Proteínas dos Microfilamentos/metabolismo , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Mutação/genética , Células de Purkinje/efeitos dos fármacos , Células de Purkinje/patologia , Proteínas de Ligação a RNA/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA