Phenylbutyrate increases SMN expression in vitro: relevance for treatment of spinal muscular atrophy.
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease, characterized by degeneration of the anterior horn cells of the spinal cord. SMA presents with a highly variable phenotype ranging from very severe to mild (type I-III). No cure for SMA is available at present. All forms of SMA are caused by homozygous loss of the functional survival motor neuron (SMN1) gene. However, all patients have one or more copies of the SMN2 gene, nearly identical to SMN1. Both genes encode the SMN protein but the level produced by SMN2 is insufficient to protect from disease. Increasing SMN2 gene expression could be of considerable therapeutic importance. The aim of this study was to assess whether SMN2 gene expression can be increased by 4-phenylbutyrate (PBA). Fibroblast cell cultures from 16 SMA patients affected by different clinical severities were treated with PBA, and full-length SMN2 transcripts were measured by real-time PCR. In all cell cultures, except one, PBA treatment caused an increase in full-length SMN2 transcripts, ranging from 50 to 160% in type I and from 80 to 400% in type II and III cultures. PBA was found also effective in enhancing SMN protein levels and the number of SMN-containing nuclear structures (gems). These data show that SMN expression is considerably increased by PBA, and suggest that the compound, owing also to its favorable pharmacological properties, could be a good candidate for the treatment of SMA.
Andreassi
Catia
C
Istituto di Genetica Medica, Università Cattolica S Cuore, Largo F Vito 1, Rome 00168, Italy.
Angelozzi
Carla
C
Tiziano
Francesco D
FD
Vitali
Tiziana
T
De Vincenzi
Eleonora
E
Boninsegna
Alma
A
Villanova
Marcello
M
Bertini
Enrico
E
Pini
Antonella
A
Neri
Giovanni
G
Brahe
Christina
C
D001483:Base Sequence; D015153:Blotting, Western; D018929:Cell Culture Techniques; D017362:Cyclic AMP Response Element-Binding Protein; D005260:Female; D005347:Fibroblasts / Q000737:chemistry; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D009134:Muscular Atrophy, Spinal / Q000628:therapy*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010654:Phenylbutyrates / Q000494:pharmacology* / Q000627:therapeutic use; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D014158:Transcription, Genetic
D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D010654:Phenylbutyrates; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; C526471:SMN1 protein, human; C526477:SMN2 protein, human; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; C075773:4-phenylbutyric acid