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
País de afiliação
Intervalo de ano de publicação
1.
Neurobiol Dis ; 149: 105228, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33359139

RESUMO

Disruption in copper homeostasis causes a number of cognitive and motor deficits. Wilson's disease and Menkes disease are neurodevelopmental disorders resulting from mutations in the copper transporters ATP7A and ATP7B, with ATP7A mutations also causing occipital horn syndrome, and distal motor neuropathy. A 65 year old male presenting with brachial amyotrophic diplegia and diagnosed with amyotrophic lateral sclerosis (ALS) was found to harbor a p.Met1311Val (M1311V) substitution variant in ATP7A. ALS is a fatal neurodegenerative disease associated with progressive muscle weakness, synaptic deficits and degeneration of upper and lower motor neurons. To investigate the potential contribution of the ATP7AM1311V variant to neurodegeneration, we obtained and characterized both patient-derived fibroblasts and patient-derived induced pluripotent stem cells differentiated into motor neurons (iPSC-MNs), and compared them to control cell lines. We found reduced localization of ATP7AM1311V to the trans-Golgi network (TGN) at basal copper levels in patient-derived fibroblasts and iPSC-MNs. In addition, redistribution of ATP7AM1311V out of the TGN in response to increased extracellular copper was defective in patient fibroblasts. This manifested in enhanced intracellular copper accumulation and reduced survival of ATP7AM1311V fibroblasts. iPSC-MNs harboring the ATP7AM1311V variant showed decreased dendritic complexity, aberrant spontaneous firing, and decreased survival. Finally, expression of the ATP7AM1311V variant in Drosophila motor neurons resulted in motor deficits. Apilimod, a drug that targets vesicular transport and recently shown to enhance survival of C9orf72-ALS/FTD iPSC-MNs, also increased survival of ATP7AM1311V iPSC-MNs and reduced motor deficits in Drosophila expressing ATP7AM1311V. Taken together, these observations suggest that ATP7AM1311V negatively impacts its role as a copper transporter and impairs several aspects of motor neuron function and morphology.


Assuntos
ATPases Transportadoras de Cobre/genética , ATPases Transportadoras de Cobre/metabolismo , Cobre/metabolismo , Variação Genética/fisiologia , Doença dos Neurônios Motores/genética , Doença dos Neurônios Motores/metabolismo , Animais , Animais Geneticamente Modificados , Animais Recém-Nascidos , Células Cultivadas , Cobre/farmacologia , Cobre/uso terapêutico , Relação Dose-Resposta a Droga , Drosophila , Variação Genética/efeitos dos fármacos , Células HeLa , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , Doença dos Neurônios Motores/tratamento farmacológico , Transporte Proteico/efeitos dos fármacos , Transporte Proteico/fisiologia
2.
Nat Commun ; 8(1): 2092, 2017 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-29233983

RESUMO

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disease. ALS-affected motor neurons exhibit aberrant localization of a nuclear RNA binding protein, TDP-43, into cytoplasmic aggregates, which contributes to pathology via unclear mechanisms. Here, we demonstrate that TDP-43 turnover and toxicity depend in part upon the endocytosis pathway. TDP-43 inhibits endocytosis, and co-localizes strongly with endocytic proteins, including in ALS patient tissue. Impairing endocytosis increases TDP-43 toxicity, aggregation, and protein levels, whereas enhancing endocytosis reverses these phenotypes. Locomotor dysfunction in a TDP-43 ALS fly model is also exacerbated and suppressed by impairment and enhancement of endocytic function, respectively. Thus, endocytosis dysfunction may be an underlying cause of ALS pathology.


Assuntos
Esclerose Lateral Amiotrófica/patologia , Proteínas de Ligação a DNA/metabolismo , Endocitose/fisiologia , Neurônios Motores/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Núcleo Celular/metabolismo , Modelos Animais de Doenças , Drosophila , Lobo Frontal/citologia , Lobo Frontal/patologia , Células HEK293 , Humanos , Locomoção/fisiologia , Agregação Patológica de Proteínas/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA