title: Myopathy in Marinesco-Sjögren syndrome links endoplasmic reticulum chaperone dysfunction to nuclear envelope pathology.
abstract: 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.
authors.affiliation: Institute of Neuropathology, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074, Aachen, Germany, aroos@ukaachen.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Roos
authors.forename: Stephan
authors.initials: S
authors.lastname: Buchkremer
authors.forename: Laxmikanth
authors.initials: L
authors.lastname: Kollipara
authors.forename: Thomas
authors.initials: T
authors.lastname: Labisch
authors.forename: Christian
authors.initials: C
authors.lastname: Gatz
authors.forename: Manuela
authors.initials: M
authors.lastname: Zitzelsberger
authors.forename: Eva
authors.initials: E
authors.lastname: Brauers
authors.forename: Kay
authors.initials: K
authors.lastname: Nolte
authors.forename: J Michael
authors.initials: JM
authors.lastname: Schröder
authors.forename: Janbernd
authors.initials: J
authors.lastname: Kirschner
authors.forename: Christopher Marvin
authors.initials: CM
authors.lastname: Jesse
authors.forename: Hans Hilmar
authors.initials: HH
authors.lastname: Goebel
authors.forename: Anand
authors.initials: A
authors.lastname: Goswami
authors.forename: Richard
authors.initials: R
authors.lastname: Zimmermann
authors.forename: René Peiman
authors.initials: RP
authors.lastname: Zahedi
authors.forename: Jan
authors.initials: J
authors.lastname: Senderek
authors.forename: Joachim
authors.initials: J
authors.lastname: Weis
mesh_terms: D000328:Adult; D000818:Animals; D001343:Autophagy; D002531:Cerebellum / Q000473:pathology; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009135:Muscular Diseases / Q000378:metabolism / Q000473:pathology*; D009154:Mutation; D009685:Nuclear Envelope / Q000378:metabolism / Q000473:pathology*; D034881:Nuclear Lamina / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D059748:Proteolysis; D012519:Sarcoplasmic Reticulum / Q000378:metabolism / Q000473:pathology; D013132:Spinocerebellar Degenerations / Q000378:metabolism / Q000473:pathology*; D055815:Young Adult
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D020662:Guanine Nucleotide Exchange Factors; D006360:Heat-Shock Proteins; C418483:SIL1 protein, human