Proteomic profiling of fibroblasts differentiates patients with severe, intermediate and mild spinal muscular atrophy

ABSTRACT: Most research to characterise the molecular consequences of spinal muscular atrophy (SMA) have focused on SMA I. Here, proteomic profiling of skin fibroblasts from severe (SMA I), intermediate (SMA II), or mild (SMA III) patients and age-matched controls was conducted using SWATH mass spectrometry analysis. Differentially expressed proteome 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 all SMA types included mTOR signaling, regulation of eIF2 and eIF4 signaling, and protein ubiquitination. BioLayout expression clustering identified protein profiles that discriminate or correlate with SMA severity. From these clusters, the differential expression of PYGB (SMA I), RAB3B (SMA II), and IMP1 and STAT1 (both SMA III) was verified by western blot, and transfection of SMA II fibroblasts with SMN-enhanced constructs confirmed RAB3B expression is SMN-dependent. In combination, this four-protein panel may have potential utility for stratifying patients into clinical trials or for monitoring therapeutic effectiveness. In addition, the diverse proteome profiles and pathways identified here pave the way for further studies aimed at optimising therapeutic strategies for SMA patients of differing severities.

INSTRUMENT(S): TripleTOF 5600

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Fibroblast

DISEASE(S): Muscular Atrophy

SUBMITTER: Sally Shirran  

LAB HEAD: Heidi Fuller

PROVIDER: PXD034596 | Pride | 2022-08-24

REPOSITORIES: Pride