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1.
Cell Rep ; 18(6): 1484-1498, 2017 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-28178525

RESUMO

The mechanism underlying selective motor neuron (MN) death remains an essential question in the MN disease field. The MN disease spinal muscular atrophy (SMA) is attributable to reduced levels of the ubiquitous protein SMN. Here, we report that SMN levels are widely variable in MNs within a single genetic background and that this heterogeneity is seen not only in SMA MNs but also in MNs derived from controls and amyotrophic lateral sclerosis (ALS) patients. Furthermore, cells with low SMN are more susceptible to cell death. These findings raise the important clinical implication that some SMN-elevating therapeutics might be effective in MN diseases besides SMA. Supporting this, we found that increasing SMN across all MN populations using an Nedd8-activating enzyme inhibitor promotes survival in both SMA and ALS-derived MNs. Altogether, our work demonstrates that examination of human neurons at the single-cell level can reveal alternative strategies to be explored in the treatment of degenerative diseases.


Assuntos
Doenças Neuromusculares/metabolismo , Proteínas do Complexo SMN/metabolismo , Esclerose Lateral Amiotrófica/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Neurônios Motores/metabolismo , Atrofia Muscular Espinal/metabolismo , Análise de Célula Única/métodos , Medula Espinal/metabolismo
2.
Science ; 345(6197): 688-93, 2014 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-25104390

RESUMO

Spinal muscular atrophy (SMA) is a genetic disease caused by mutation or deletion of the survival of motor neuron 1 (SMN1) gene. A paralogous gene in humans, SMN2, produces low, insufficient levels of functional SMN protein due to alternative splicing that truncates the transcript. The decreased levels of SMN protein lead to progressive neuromuscular degeneration and high rates of mortality. Through chemical screening and optimization, we identified orally available small molecules that shift the balance of SMN2 splicing toward the production of full-length SMN2 messenger RNA with high selectivity. Administration of these compounds to Δ7 mice, a model of severe SMA, led to an increase in SMN protein levels, improvement of motor function, and protection of the neuromuscular circuit. These compounds also extended the life span of the mice. Selective SMN2 splicing modifiers may have therapeutic potential for patients with SMA.


Assuntos
Processamento Alternativo/efeitos dos fármacos , Cumarínicos/administração & dosagem , Isocumarinas/administração & dosagem , Longevidade/efeitos dos fármacos , Atrofia Muscular Espinal/tratamento farmacológico , Pirimidinonas/administração & dosagem , Bibliotecas de Moléculas Pequenas/administração & dosagem , Proteína 2 de Sobrevivência do Neurônio Motor/genética , Administração Oral , Animais , Células Cultivadas , Cumarínicos/química , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Isocumarinas/química , Camundongos , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/metabolismo , Pirimidinonas/química , RNA Mensageiro/genética , Deleção de Sequência , Bibliotecas de Moléculas Pequenas/química , Proteína 2 de Sobrevivência do Neurônio Motor/metabolismo
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