gms | German Medical Science

57. Jahrestagung der Deutschen Gesellschaft für Neuropathologie und Neuroanatomie (DGNN)

Deutsche Gesellschaft für Neuropathologie und Neuroanatomie

12. - 15.09.2012, Erlangen

Banner: 57. Jahrestagung der Deutschen Gesellschaft für Neuropathologie und Neuroanatomie

“Woozy” mice are a broad phenocopy of human Marinesco-Sjögren syndrome: an electron microscopic and biochemical longitudinal study

Meeting Abstract

  • presenting/speaker Andreas Roos - University Hospital RWTH Aachen, Institute of Neuropathology, Aachen, Germany
  • Stephan Buchkremer - University Hospital RWTH Aachen, Institute of Neuropathology, Aachen, Germany
  • Anand Goswami - University Hospital RWTH Aachen, Institute of Neuropathology, Aachen, Germany
  • Kay Nolte - University Hospital RWTH Aachen, Institute of Neuropathology, Aachen, Germany
  • Jan Senderek - Friedrich-Baur-Institute, Munich, Germany
  • Eva Brauers - University Hospital RWTH Aachen, Institute of Neuropathology, Aachen, Germany
  • Joachim Weis - University Hospital RWTH Aachen, Institute of Neuropathology, Aachen, Germany

Deutsche Gesellschaft für Neuropathologie und Neuroanatomie. 57th Annual Meeting of the German Society for Neuropathology and Neuroanatomy (DGNN). Erlangen, 12.-15.09.2012. Düsseldorf: German Medical Science GMS Publishing House; 2012. Doc12dgnnPP1.5

DOI: 10.3205/12dgnn023, URN: urn:nbn:de:0183-12dgnn0236

Veröffentlicht: 11. September 2012

© 2012 Roos et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielfältigt, verbreitet und öffentlich zugänglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

Text

Mutations in the humanSIL1gene and disruption of the murineSil1gene, both encoding the endoplasmic reticulum (ER) resident co-chaperone Sil1, were identified as a major cause of MSS and of the “woozy”-mouse phenotype, respectively. Marinesco-Sjögren syndrome (MSS) is a rare progressive multisystem disorder with autosomal recessive inheritance. The human phenotype is characterized by cerebellar ataxia, congenital or infantile cataracts, progressive vacuolar myopathy with peculiar myonuclear alterations, mental retardation, and short stature. However, in “woozy” mice, solely the cerebellar atrophy (due to a loss of Purkinje cells and resulting in ataxia) has been described so far. In both phenotypes, loss of Sil1 results in the buildup of misfolded proteins in the endoplasmic reticulum of the affected tissues, which induces a protective reaction known as the unfolded protein response (UPR). In a longitudinal study, we investigated thevastusmuscles of 16-, 26-, 84- and 100-weeks old “woozy”-animals and of healthy wild-type littermates using electron microscopy and biochemical methods. We found marked myopathy in the mouse model, similar to the peculiar myopathic changes in human muscle and including the MSS-specific alterations of the sarcoplasmic reticulum. In the mouse model we were able to study the age-dependent manifestation of the myopathic alterations. On the biochemical level, we found a induction of the UPR in thevastusmuscles of Sil1-deficient mice. Moreover, we generated two SIL1-deficient mammalian cell lines, which serve as MSS cell culture models. In these cell lines, both electron microscopic and biochemical studies revealed changes similar to the alterations detected in the muscles of MSS patients and “woozy”mice. Herein, we report for the first time a distinct skeletal muscle phenotype in the MSS animal model “woozy”. The muscle changes are age-dependent and are morphologically and biochemically similar to the human MSS phenotype. Our findings link MSS myopathy to disturbances in the homeostasis of the sarcoplasmic reticulum, resulting in the activation of the UPR. The “woozy”-mouse model therefore is a broad phenocopy of MSS. Our mammalian cell lines showing similar alterations confirm our results and provide a suitablein vitromodel for the preclinical testing of therapeutic strategies.