Novel aminoglycosides increase SMN levels in spinal muscular atrophy fibroblasts.
Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality. SMA is caused by the homozygous absence of survival motor neuron-1 (SMN1). SMN2, a nearly identical copy gene, is retained in all SMA patients and encodes an identical protein as SMN1; however, SMN1 and SMN2 differ by a silent C to T transition which results in the production of an alternatively spliced isoform (SMNDelta7), which encodes a defective protein, demonstrating that the absence of the short peptide encoded by SMN exon 7 is critical in SMA development. Previously, we have shown that for some functions heterologous sequences can compensate for the exon 7 peptide, suggesting that the SMN C-terminus functions non-specifically. Consistent with this hypothesis, we now identify novel aminoglycosides that can induce SMN protein levels in patient fibroblasts. This hypothesis was supported, in part, by a novel fluorescent SMN read-through assay. Interestingly, however, through the development of a SMN exon 7-specific antibody, results suggested that levels of normal full-length SMN might also be elevated by aminoglycoside treatment. These results demonstrate that the compounds that promote read-through may provide an alternative platform for the discovery of compounds that induce SMN protein levels.
Mattis
Virginia B
VB
Department of Veterinary Pathobiology, Life Sciences Center, University of Missouri, Room 471G, Columbia, MO 65211-7310, USA.
Rai
Ravi
R
Wang
Jinhua
J
Chang
Cheng-Wei T
CW
Coady
Tristan
T
Lorson
Christian L
CL
D000617:Aminoglycosides / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005091:Exons; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D015394:Molecular Structure; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D012326:RNA Splicing / Q000187:drug effects; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055532:SMN Complex Proteins; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D013997:Time Factors; D014162:Transfection
D000617:Aminoglycosides; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion 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; D049452:Green Fluorescent Proteins; D008156:Luciferases; D051548:Histone Acetyltransferases