Universität zu Köln

Brown, Sharon J., Kline, Rachel A., Synowsky, Silvia A., Shirran, Sally L., Holt, Ian, Sillence, Kelly A., Claus, Peter ORCID: 0000-0003-3824-9445, Wirth, Brunhilde ORCID: 0000-0003-4051-5191, Wishart, Thomas M. and Fuller, Heidi R. (2022). The Proteome Signatures of Fibroblasts from Patients with Severe, Intermediate and Mild Spinal Muscular Atrophy Show Limited Overlap. Cells, 11 (17). BASEL: MDPI. ISSN 2073-4409

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Brown, Sharon J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kline, Rachel A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Synowsky, Silvia A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Shirran, Sally L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Holt, Ian UNSPECIFIED UNSPECIFIED UNSPECIFIED Sillence, Kelly A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Claus, Peter UNSPECIFIED orcid.org/0000-0003-3824-9445 UNSPECIFIED Wirth, Brunhilde UNSPECIFIED orcid.org/0000-0003-4051-5191 UNSPECIFIED Wishart, Thomas M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fuller, Heidi R. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-687671
DOI:	10.3390/cells11172624
Journal or Publication Title:	Cells
Volume:	11
Number:	17
Date:	2022
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	2073-4409
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MITOCHONDRIAL DYSFUNCTION; SMN EXPRESSION; GENE-PRODUCT; MOUSE MODEL; SURVIVAL; DISEASE; PHENOTYPE; CELLS; REQUIREMENT; MANAGEMENT Multiple languages Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68767