New insights into the protein aggregation pathology in myotilinopathy by combined proteomic and immunolocalization analyses


INTRODUCTION Myofibrillar myopathies are characterized by progressive muscle weakness and impressive abnormal protein aggregation in muscle fibers. In about 10 % of patients, the disease is caused by mutations in the MYOT gene encoding myotilin. The aim of our study was to decipher the composition of protein deposits in myotilinopathy to get new information about aggregate pathology. RESULTS Skeletal muscle samples from 15 myotilinopathy patients were included in the study. Aggregate and control samples were collected from muscle sections by laser microdissection and subsequently analyzed by a highly sensitive proteomic approach that enables a relative protein quantification. In total 1002 different proteins were detected. Seventy-six proteins showed a significant over-representation in aggregate samples including 66 newly identified aggregate proteins. Z-disc-associated proteins were the most abundant aggregate components, followed by sarcolemmal and extracellular matrix proteins, proteins involved in protein quality control and degradation, and proteins with a function in actin dynamics or cytoskeletal transport. Forty over-represented proteins were evaluated by immunolocalization studies. These analyses validated our mass spectrometric data and revealed different regions of protein accumulation in abnormal muscle fibers. Comparison of data from our proteomic analysis in myotilinopathy with findings in other myofibrillar myopathy subtypes indicates a characteristic basic pattern of aggregate composition and resulted in identification of a highly sensitive and specific diagnostic marker for myotilinopathy. CONCLUSIONS Our findings i) indicate that main protein components of aggregates belong to a network of interacting proteins, ii) provide new insights into the complex regulation of protein degradation in myotilinopathy that may be relevant for new treatment strategies, iii) imply a combination of a toxic gain-of-function leading to myotilin-positive protein aggregates and a loss-of-function caused by a shift in subcellular distribution with a deficiency of myotilin at Z-discs that impairs the integrity of myofibrils, and iv) demonstrate that proteomic analysis can be helpful in differential diagnosis of protein aggregate myopathies.

DOI: 10.1186/s40478-016-0280-0

Extracted Key Phrases

Citations per Year

605 Citations

Semantic Scholar estimates that this publication has 605 citations based on the available data.

See our FAQ for additional information.

Cite this paper

@inproceedings{Maerkens2016NewII, title={New insights into the protein aggregation pathology in myotilinopathy by combined proteomic and immunolocalization analyses}, author={Alexandra Maerkens and M. Oliv{\'e} and Anja Schreiner and Sarah Feldkirchner and Joachim Schessl and Julian Uszkoreit and Katalin Barkovits and Anne K G{\"{u}ttsches and Verena Theis and Martin Eisenacher and Martin Tegenthoff and Lev G. Goldfarb and Rolf Schr{\"{o}der and Benedikt Schoser and Peter F. M. van der Ven and Dieter O. F{\"{u}rst and Matthias Vorgerd and Katrin Marcus and Rudolf Andr{\'e} Kley}, booktitle={Acta neuropathologica communications}, year={2016} }