Research Papers:

In-depth phenotyping of lymphoblastoid cells suggests selective cellular vulnerability in Marinesco-Sjögren syndrome

Laxmikanth Kollipara, Stephan Buchkremer, José Andrés González Coraspe, Denisa Hathazi, Jan Senderek, Joachim Weis, René P. Zahedi and Andreas Roos _

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Oncotarget. 2017; 8:68493-68516. https://doi.org/10.18632/oncotarget.19663

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Laxmikanth Kollipara1,*, Stephan Buchkremer2,*, José Andrés González Coraspe2, Denisa Hathazi1, Jan Senderek3, Joachim Weis2, René P. Zahedi1,** and Andreas Roos1,2,4,**

1Leibniz-Institut für Analytische Wissenschaften–ISAS –e.V., 44227 Dortmund, Germany

2Institute of Neuropathology, University Hospital Aachen, RWTH Aachen, 5274 Aachen, Germany

3Friedrich-Baur-Institute, Medical Faculty, Ludwig-Maximilians-University, 80336 Munich, Germany

4The John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK

*First authors contributed equally to this work

**Senior authors contributed equally to this work

Correspondence to:

Andreas Roos, email: [email protected], [email protected]

Keywords: Marinesco-Sjögren syndrome, woozy mouse, SIL1, ataxin-10, chaperonopathy

Received: May 03, 2016     Accepted: May 28, 2017     Published: July 28, 2017


SIL1 is a ubiquitous protein of the Endoplasmic Reticulum (ER) acting as a co-chaperone for the ER-resident chaperone, BiP. Recessive mutations of the corresponding gene lead to vulnerability of skeletal muscle and central nervous system in man (Marinesco-Sjögren syndrome; MSS) and mouse. However, it is still unclear how loss of ubiquitous SIL1 leads to selective vulnerability of the nervous system and skeletal muscle whereas other cells and organs are protected from clinical manifestations. In this study we aimed to disentangle proteins participating in selective vulnerability of SIL1-deficient cells and tissues: morphological examination of MSS patient-derived lymphoblastoid cells revealed altered organelle structures (ER, nucleus and mitochondria) thus showing subclinical vulnerability. To correlate structural perturbations with biochemical changes and to identify proteins potentially preventing phenotypical manifestation, proteomic studies have been carried out. Results of proteomic profiling are in line with the morphological findings and show affection of nuclear, mitochondrial and cytoskeletal proteins as well as of such responsible for cellular viability. Moreover, expression patterns of proteins known to be involved in neuromuscular disorders or in development and function of the nervous system were altered. Paradigmatic findings were confirmed by immunohistochemistry of splenic lymphocytes and the cerebellum of SIL1-deficient mice. Ataxin-10, identified with increased abundance in our proteome profile, is necessary for the neuronal survival but also controls muscle fiber apoptosis, thus declaring this protein as a plausible candidate for selective tissue vulnerability. Our combined results provide first insights into the molecular causes of selective cell and tissue vulnerability defining the MSS phenotype.

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