title: Differential proteomic analysis of abnormal intramyoplasmic aggregates in desminopathy.
abstract: Desminopathy is a subtype of myofibrillar myopathy caused by desmin mutations and characterized by protein aggregates accumulating in muscle fibers. The aim of this study was to assess the protein composition of these aggregates. Aggregates and intact myofiber sections were obtained from skeletal muscle biopsies of five desminopathy patients by laser microdissection and analyzed by a label-free spectral count-based proteomic approach. We identified 397 proteins with 22 showing significantly higher spectral indices in aggregates (ratio >1.8, p<0.05). Fifteen of these proteins not previously reported as specific aggregate components provide new insights regarding pathomechanisms of desminopathy. Results of proteomic analysis were supported by immunolocalization studies and parallel reaction monitoring. Three mutant desmin variants were detected directly on the protein level as components of the aggregates, suggesting their direct involvement in aggregate-formation and demonstrating for the first time that proteomic analysis can be used for direct identification of a disease-causing mutation in myofibrillar myopathy. Comparison of the proteomic results in desminopathy with our previous analysis of aggregate composition in filaminopathy, another myofibrillar myopathy subtype, allows to determine subtype-specific proteomic profile that facilitates identification of the specific disorder.
  
  
  CONCLUSIONS
  Our proteomic analysis provides essential new insights in the composition of pathological protein aggregates in skeletal muscle fibers of desminopathy patients. The results contribute to a better understanding of pathomechanisms in myofibrillar myopathies and provide the basis for hypothesis-driven studies. The detection of specific proteomic profiles in different myofibrillar myopathy subtypes indicates that proteomic analysis may become a useful tool in differential diagnosis of protein aggregate myopathies.
authors: Department of Neurology, Neuromuscular Centre Ruhrgebiet, University Hospital Bergmannsheil, Ruhr-University Bochum, Bochum, Germany.
authors: A
authors: A
authors: Maerkens
authors: R A
authors: RA
authors: Kley
authors: M
authors: M
authors: Olivé
authors: V
authors: V
authors: Theis
authors: P F M
authors: PF
authors: van der Ven
authors: J
authors: J
authors: Reimann
authors: H
authors: H
authors: Milting
authors: A
authors: A
authors: Schreiner
authors: J
authors: J
authors: Uszkoreit
authors: M
authors: M
authors: Eisenacher
authors: K
authors: K
authors: Barkovits
authors: A K
authors: AK
authors: Güttsches
authors: J
authors: J
authors: Tonillo
authors: K
authors: K
authors: Kuhlmann
authors: H E
authors: HE
authors: Meyer
authors: R
authors: R
authors: Schröder
authors: M
authors: M
authors: Tegenthoff
authors: D O
authors: DO
authors: Fürst
authors: T
authors: T
authors: Müller
authors: L G
authors: LG
authors: Goldfarb
authors: M
authors: M
authors: Vorgerd
authors: K
authors: K
authors: Marcus
mesh_terms: D000328:Adult; D000368:Aged; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000473:pathology; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009136:Muscular Dystrophies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D020543:Proteome / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics
chemical_list: D009124:Muscle Proteins; D020543:Proteome
keywords: AUC; BSA; CSDA; DES; Desminopathy; FA; FDR; FHL1; FLNC; Filaminopathy; Hsp; LMD; Laser microdissection; MFM; Mass spectrometry; Myofibrillar myopathy; N-RAP; Nebulin-related-anchoring protein; PET; PRM; PSM; Parallel reaction monitoring; RBM; RT; SI; SRM; Xin; Xin actin-binding repeat-containing protein 1; Xin actin-binding repeat-containing protein 2; Xirp2; area under the curve; bovine serum albumin; cold shock domain protein A; desmin; false discovery rate; filamin C; formic acid; four and a half LIM domains protein 1; heat shock protein; laser microdissection; myofibrillar myopathy; parallel reaction monitoring; peptide spectrum match; polyethylene terephthalate; reducing body myopathy; room temperature; single reaction monitoring; spectral index
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