Myopathy in Marinesco–Sjögren syndrome links endoplasmic reticulum chaperone dysfunction to nuclear envelope pathology
| Autor: | Hans H. Goebel, Stephan Buchkremer, Janbernd Kirschner, Jan Senderek, Thomas Labisch, René P. Zahedi, Laxmikanth Kollipara, Joachim Weis, Christopher Marvin Jesse, Anand Goswami, Andreas Roos, Manuela Zitzelsberger, Richard Zimmermann, Kay Nolte, Eva Brauers, Christian Gatz, J. Michael Schröder |
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| Rok vydání: | 2013 |
| Předmět: |
Adult
Male Pathology medicine.medical_specialty Nuclear Envelope Marinesco–Sjögren syndrome Pathology and Forensic Medicine Mice Young Adult Cellular and Molecular Neuroscience Muscular Diseases Cerebellum Autophagy medicine Animals Guanine Nucleotide Exchange Factors Humans Muscle Skeletal Myopathy Endoplasmic Reticulum Chaperone BiP Heat-Shock Proteins Spinocerebellar Degenerations Phenocopy Nuclear Lamina biology Endoplasmic reticulum Skeletal muscle medicine.disease Disease Models Animal Sarcoplasmic Reticulum Phenotype medicine.anatomical_structure Chaperone (protein) Mutation Proteolysis biology.protein Unfolded protein response Nuclear lamina Female Neurology (clinical) medicine.symptom |
| Zdroj: | Acta Neuropathologica. 127:761-777 |
| ISSN: | 1432-0533 0001-6322 |
| DOI: | 10.1007/s00401-013-1224-4 |
| Popis: | Marinesco-Sjögren syndrome (MSS) features cerebellar ataxia, mental retardation, cataracts, and progressive vacuolar myopathy with peculiar myonuclear alterations. Most MSS patients carry homozygous or compound heterozygous SIL1 mutations. SIL1 is a nucleotide exchange factor for the endoplasmic reticulum resident chaperone BiP which controls a plethora of essential processes in the endoplasmic reticulum. In this study we made use of the spontaneous Sil1 mouse mutant woozy to explore pathomechanisms leading to Sil1 deficiency-related skeletal muscle pathology. We found severe, progressive myopathy characterized by alterations of the sarcoplasmic reticulum, accumulation of autophagic vacuoles, mitochondrial changes, and prominent myonuclear pathology including nuclear envelope and nuclear lamina alterations. These abnormalities were remarkably similar to the myopathy in human patients with MSS. In particular, the presence of perinuclear membranous structures which have been reported as an ultrastructural hallmark of MSS-related myopathy could be confirmed in woozy muscles. We found that these structures are derived from the nuclear envelope and nuclear lamina and associate with proliferations of the sarcoplasmic reticulum. In line with impaired function of BiP secondary to loss of its nucleotide exchange factor Sil1, we observed activation of the unfolded protein response and the endoplasmic-reticulum-associated protein degradation-pathway. Despite initiation of the autophagy-lysosomal system, autophagic clearance was found ineffective which is in agreement with the formation of autophagic vacuoles. This report identifies woozy muscle as a faithful phenocopy of the MSS myopathy. Moreover, we provide a link between two well-established disease mechanisms in skeletal muscle, dysfunction of chaperones and nuclear envelope pathology. |
| Databáze: | OpenAIRE |
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