The proteome signatures of fibroblasts from patients with severe, intermediate and mild spinal muscular atrophy show limited overlap
Abstract
Most research to characterise the molecular consequences of spinal muscular atrophy (SMA) has focused on SMA I. Here, proteomic profiling of skin fibroblasts from severe (SMA I), intermediate (SMA II), and mild (SMA III) patients, alongside age-matched controls, was conducted using SWATH mass spectrometry analysis. Differentially expressed proteomic profiles showed limited overlap across each SMA type, and variability was greatest within SMA II fibroblasts, which was not explained by SMN2 copy number. Despite limited proteomic overlap, enriched canonical pathways common to two of three SMA severities with at least one differentially expressed protein from the third included mTOR signalling, regulation of eIF2 and eIF4 signalling, and protein ubiquitination. Network expression clustering analysis identified protein profiles that may discriminate or correlate with SMA severity. From these clusters, the differential expression of PYGB (SMA I), RAB3B (SMA II), and IMP1 and STAT1 (SMA III) was verified by Western blot. All SMA fibroblasts were transfected with an SMN-enhanced construct, but only RAB3B expression in SMA II fibroblasts demonstrated an SMN-dependent response. The diverse proteomic profiles and pathways identified here pave the way for studies to determine their utility as biomarkers for patient stratification or monitoring treatment efficacy and for the identification of severity-specific treatments.
Citation
Brown , S J , Kline , R A , Synowsky , S A , Shirran , S L , Holt , I , Sillence , K A , Claus , P , Wirth , B , Wishart , T M & Fuller , H R 2022 , ' The proteome signatures of fibroblasts from patients with severe, intermediate and mild spinal muscular atrophy show limited overlap ' , Cells , vol. 11 , no. 17 , 2624 . https://doi.org/10.3390/cells11172624
Publication
Cells
Status
Peer reviewed
ISSN
2073-4409Type
Journal article
Description
This work was supported by Great Ormond Street Hospital Charity (GOSH) and SPARKS Children’s Medical Research Charity (Grant No. V5018 to H.R.F.). Electroporator funded by the Orthopaedic Institute Ltd. (One liner fund). R.A.K. was funded by the Euan Macdonald Centre for Motor Neuron Disease Research Ph.D. studentship and the University of Edinburgh’s Principal’s Career Development and Global Research scholarships. T.M.W. is supported by funding from the Biotechnology and Biological Sciences Research Council (BBSRC) Institute Strategic Grant (BBS/E/D/10002071). B.W.’s research on spinal muscular atrophy and the generation of cell lines was supported by the German Research Foundation [Wi 945/17-1 (project-ID 398410809); SFB1451 (project-ID 431549029—A01)] and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 956185 (SMABEYOND).Collections
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