A screen for regulators of survival of motor neuron protein levels.
Nat Chem Biol
; 7(8): 544-52, 2011 Jun 19.
Article
em En
| MEDLINE
| ID: mdl-21685895
ABSTRACT
The motor neuron disease spinal muscular atrophy (SMA) results from mutations that lead to low levels of the ubiquitously expressed protein survival of motor neuron (SMN). An ever-increasing collection of data suggests that therapeutics that elevate SMN may be effective in treating SMA. We executed an image-based screen of annotated chemical libraries and discovered several classes of compounds that were able to increase cellular SMN. Among the most important was the RTK-PI3K-AKT-GSK-3 signaling cascade. Chemical inhibitors of glycogen synthase kinase 3 (GSK-3) and short hairpin RNAs (shRNAs) directed against this target elevated SMN levels primarily by stabilizing the protein. It was particularly notable that GSK-3 chemical inhibitors were also effective in motor neurons, not only in elevating SMN levels, but also in blocking the death that was produced when SMN was acutely reduced by an SMN-specific shRNA. Thus, we have established a screen capable of detecting drug-like compounds that correct the main phenotypic change underlying SMA.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Atrofia Muscular Espinal
/
Regulação da Expressão Gênica
/
Proteína 1 de Sobrevivência do Neurônio Motor
/
Descoberta de Drogas
Limite:
Adult
/
Animals
/
Child, preschool
/
Humans
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article