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Myopathy in Marinesco–Sjögren syndrome links endoplasmic reticulum chaperone dysfunction to nuclear envelope pathology

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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.

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Acknowledgments

We thank Hannelore Mader, Astrid Knischewski, Claudia Krude, Elke Beck, Hannelore Wiederhold, and Evelyne Pascual for expert technical assistance. We also thank Torsten Rollar for expert IT assistance. This work has been supported by a grant from START program of RWTH Aachen University (to A. R.; Grant No. 41/12), by the Else Kröner-Fresenius Stiftung (to A. R.; Grant No. A59/09), by the Ministerium für Innovation, Wissenschaft und Forschung des Landes Nordrhein-Westfalen, by a grant from the Maximilian-May-Stiftung (to J. S.) and grants by the German Research Foundation (DFG; WE 1406/13-1 and ZA 639/1-1) and the IZKF Aachen (to J. W.; Grant No. N5-3). Purchase of woozy animals was funded by the HOMFOR program.

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  1. Institute of Neuropathology, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074, Aachen, Germany

    Andreas Roos, Stephan Buchkremer, Thomas Labisch, Christian Gatz, Eva Brauers, Kay Nolte, J. Michael Schröder, Christopher Marvin Jesse, Anand Goswami & Joachim Weis

  2. JARA-Translational Brain Medicine, 52074, Aachen, Germany

    Andreas Roos, Stephan Buchkremer, Thomas Labisch, Christian Gatz, Eva Brauers, Kay Nolte, J. Michael Schröder, Christopher Marvin Jesse, Anand Goswami & Joachim Weis

  3. Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., Otto-Hahn-Str. 6b, 44227, Dortmund, Germany

    Laxmikanth Kollipara & René Peiman Zahedi

  4. Friedrich-Baur-Institute, Ludwig-Maximilians-University, Ziemssenstr. 1a, 80336, Munich, Germany

    Manuela Zitzelsberger & Jan Senderek

  5. Division of Neuropediatrics and Muscle Disorders, Center for Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Mathildenstr. 1, 79106, Freiburg, Germany

    Janbernd Kirschner

  6. Department of Neuropathology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany

    Hans Hilmar Goebel

  7. Institute of Medical Biochemistry and Molecular Biology, University of Saarland, Kirrbergerstr. Building 44, 66424, Homburg, Germany

    Richard Zimmermann

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Supplementary material 2 (DOC 270 kb)

401_2013_1224_MOESM3_ESM.ppt

Suppl. Fig. 1 Cryostat section histology of human and mouse muscle and macroscopic appearance of wz mouse hind limbs. (a) Vacuolar myopathy in the muscle biopsy of patient MSS33. Arrows: subsarcolemmal autophagic vacuoles, Gomori trichrome; scale bar = 23 μm. (b) Normal muscle fibers in 16 wk old wt mouse quadriceps muscle. PAS; scale bar = 26 μm. (c) Largely normal light microscopical appearance of wz littermate mouse quadriceps muscle at 16 weeks of age. Arrow: non-subsarcolemmal myonucleus. PAS; scale bar = 26 μm. (d) Tubular aggregates (arrow) in otherwise normal muscle fibers of an 84-week-old wt mouse. H&E; scale bar = 25 μm. (e) Vacuolar myopathy with highly variable muscle fiber calibers and nseveral non-subsarcolemmal myonuclei in wz littermate mouse. Arrows: rimmed vacuoles associated with myonuclear degeneration. H&E; scale bar = 20 μm. Inset: another rimmed vacuole with degenerated myonucleus. H&E; scale bar = 20 μm. (f) Tubular aggregates (red; arrow) in the 84-week-old wt mouse. Gomori trichrome; scale bar = 20 μm. (g) Condensed myonuclei (white arrow) in a damaged muscle fiber of the 84-week-old wz mouse. Black arrow: Subsarcolemmal rimmed vacuole, possibly associated with myonucleus. Tubular aggregates were absent from this muscle. Gomori trichrome; scale bar = 15 μm. (h) Normal muscle fibers of a 100-week-old wt mouse. H&E; scale bar = 25 μm. (i) Prominent vacuolar myopathy characterized by fiber atrophy and splitting (black arrow), moderate endomysial fibrosis and numerous non-subsarcolemmal muscle fiber nuclei as well as autophagic vacuoles derived from degenerating myonuclei (white arrows) in a 100-week-old wz littermate. H&E; scale bar in (i) = 20 μm and in inset = 15 μm. (j and l) Normal macroscopic appearance of hind limb muscle (black arrows: quadriceps muscle) in an 84- and a 100-week-old wt mouse. White arrows: normal fat tissue. (k and m) Reduced muscle bulk and vanished fat tissue in wz littermates. (PPT 449 kb)

401_2013_1224_MOESM4_ESM.ppt

Suppl. Fig. 2 Further histopathological findings in semithin sections of glutaraldehyde-fixed, epoxy resin-embedded muscle biopsy specimens of MSS patients (a and b) and wz mice (c-h). (a) Autophagic vacuole in the perinuclear sarcoplasm of a muscle fiber in the biopsy of MSS patient 3 (black arrow). White arrows: myofibrillar disintegration associated with prominent Z-Band streaming. Scale bar = 18 μm. (b) Large subsarcolemmal autophagic vacuole in a muscle fiber in the biopsy of MSS patient 33 (black arrow). Scale bar = 20 μm. (c) Muscle fibers without structural abnormalities and with normal nuclei in a 16-week-old control mouse. Longitudinal section. Scale bar = 20 μm. (d and e) Autophagic vacuoles in the perinuclear sarcoplasm of a muscle fiber of a 16-week-old wz mouse (black arrows). Scale bar in e = 15 μm, in f = 10 μm. (f and g) Increased number of non-subsarcolemmal nuclei in muscle fibers of 26-week-old wz mice (white arrows). Black arrows: autophagic vacuoles. Scale bar in g = 25 μm, in h = 20 μm. (Inset in h) Abnormal non-subsarcolemmal myonucleus (white arrow) with condensed chromatin and perinuclear membranous structure. Scale bar = 13 μm. (h) Large granular material in myonuclei of an 84-week-old wz mouse. Gray arrow: accumulation of moderately osmiophilic material (glycogen and mitochondria) in a large muscle fiber. Black arrow and inset: prominent subsarcolemmal myonuclei with remodeled chromatin. Scale bars in main figure and in inset = 20 μm. (PPT 7562 kb)

401_2013_1224_MOESM5_ESM.ppt

Suppl. Fig. 3 Ultrastructural alterations in wz mouse muscle at age 16 weeks analyzed by transmission electron microscopy. (a) Focal widening of the SR (black arrows) associated with accumulated autophagic material (white arrow). Scale bar = 2.5 μm. (b and c) Subsarcolemmal enlargements of SR. Scale bars = 0.8 μm (b) and 1.2 μm (c). (d) Mitochondria engulfed by multiple osmiophilic membranes indicating early mitophagia (black arrow). Scale bar = 0.7 μm. μm. (e) Membranous inclusion in muscle fiber mitochondrion (black arrow). White arrow: widened SR tubules. Scale bar = 0.5 μm. (f) Large perinuclear autophagic vacuole containing myelin-like osmiophilic material (black arrows) engulfing tubulovesicular structures, presumably SR. Scale bar = 1.3 μm. (g) Membranous autophagic material (black arrow) in the perinuclear sarcoplasm. Scale bar = 3.5 μm. (h) Larger accumulation of subsarcolemmal membranous autophagic material in another muscle fiber. Scale bar = 2.5 μm. (i) Perinuclear proliferation of membranous and tubular structures of presumed SR origin evolving into myelin-like autophagic material (black arrows) surrounding a non-subsarcolemmal myonucleus. White arrows: enlarged, swollen mitochondria. Scale bar = 4 μm. (j) Perinuclear SR membrane proliferation (black arrows). Scale bar = 1.5 μm. (k) Membrane outfolding (black arrow) continuous with the nuclear envelope. Scale bar = 0.4 μm. (l) Lobulated myonucleus surrounded by membrane proliferations and membranous (black arrow) and granular autophagic material. Scale bar = 1.5 μm. (m) Markedly condensed chromatin especially at the nuclear membrane in a pyknotic myonucleus. Scale bar = 2.0 μm. (n) Subsarcolemmal myonucleus showing chromatin condensation at the nuclear membrane accompanied by two perinuclear autophagic vacuoles. Scale bar = 7 μm. (PPT 3728 kb)

401_2013_1224_MOESM6_ESM.ppt

Suppl. Fig. 4 Ultrastructural alterations in wz mouse muscle at age 26 weeks analyzed by transmission electron microscopy. (a) Myonucleus showing chromatin condensation at the nuclear envelope. Black arrows: perinuclear SR tubule and membrane proliferation. (M): enlarged, swollen mitochondrion. Scale bar = 2.0 μm. (b) Prominently widened SR (black arrows). Scale bar = 2.5 μm. (c) Focal myonuclear lobulation (black arrows). (M): swollen mitochondria in an adjacent muscle fiber. Scale bar = 2.0 μm. (d) Late stage of myonuclear degeneration (black arrow). Scale bar = 3.0 μm. (e) Pronounced lobulation of a myonucleus. Scale bar = 2.0 μm. (f) Large subsarcolemmal autophagic vacuole containing myelin-like osmiophilic material. Scale bar = 2 μm. (g) Condensed muscle fiber mitochondrion (black arrow) engulfed by osmiophilic membranes, indicating mitophagia. Scale bar = 0.3 μm. (h) Large subsarcolemmal autophagic vacuole containing granular and membranous autophagic material. Black arrow: remanants of a myonucleus. Scale bar = 1.8 μm. (i) Autophagic vacuole containing myelin-like osmiophilic material. Scale bar = 2 μm. (j) Focal lift off of (leaflet of) the envelope (black arrows) of a myonucleus with markedly condensed chromatin. Scale bar = 0.8 μm. (k) Another myonucleus showing similar alterations of the envelope (black arrow). Scale bar = 1.8 μm. (l) Lobulated myonucleus with adjacent autophagic material (black arrow). Scale bar = 0.5 μm. (m) Centralized myonuclei one of which is showing pronounced chromatin condensation (black arrow). Scale bar = 4.0 μm. (PPT 2499 kb)

401_2013_1224_MOESM7_ESM.ppt

Suppl. Fig. 5 Ultrastructural alterations in wz mouse muscle at age 84 weeks. (a, b) Prominent focal widening of the SR (black arrows). Scale bar = 2.5 μm. (c, d) Focal mitochondrial swelling (black arrows). Scale bar = in (c) = 1 μm, in (d) 0.7 μm. (e-i) Membranous perinuclear autophagic material (black arrows). Scale bars = 1.2 μm in (e–g), 2.5 μm in (h), 1.5 μm in (i). (j-n) Lift-off, outfolding and extension of nuclear envelope (black arrows) of several degenerating myonuclei partially combined with marked proliferation of other membranous as well widened and proliferated tubular (SR) structures (white arrows). Scale bars in (j and k) = 4 μm, in (l) 3 μm, in (m and n) = 2 μm. (PPT 5972 kb)

401_2013_1224_MOESM8_ESM.ppt

Suppl. Fig. 6 Cerebellar alterations in wz mice. (a) Normal density of Purkinje cells (white arrows) and absence of glial cell proliferation in the wt littermate control. Scale bar = 40 μm. (b) Single remaining Purkinje cell (white arrow); black arrows: proliferated (Bergmann) glial cells in a 26-week-old wz mouse. Scale bar = 40 μm. (PPT 440 kb)

401_2013_1224_MOESM9_ESM.ppt

Suppl. Fig. 7 (e) Further analysis of selected proteins in three animal pairs at age 26 weeks. Presence of muscle fiber ER stress, activation of UPR and ERAD pathway as well as of lysosomal–autophagy could be confirmed by alterations in paradigmatic factors in the three pairs. GAPDH was used as loading control and as normalization factor for protein increase studies (upper bar graph). Results are consistent throughout all different ages of animals analyzed (16 weeks, 26 weeks, 52 weeks and 84 weeks). Quantification of the three independent experiments is shown. Y-axis shows fold of increase. X-axis shows proteins analyzed. Student′s unpaired t test was used. P values were as following: Atf6(uncleaved) = 0.0413*; Atf6(cleaved) = 0.0010***; Becn1 = 0,0094**; BiP = 0,0743; Chop = 0,0942; eif2α = 0,8722; peif2α = 0,0112*; Dnajb6 = 0,3678; Grp170 = 0,1122; Lc3-I = 0,0001***; Lc3-II = 0,9842; Lmna = 0,0956; Lmnb1 = 0,0201*; Pdi = 0,0939; Perk = 0.2269; pPerk = 0,1495; Rab11 = 0,0393*; Sec62 = 0,0246*; Tdp-43 = 0,0058**; Vcp = 0,0022**. * significant greater or lower than control value; ** very significant greater or lower than control value; *** extremely significant greater or lower than control value. Lower bar graph shows average ratios of protein activation (phosphorylation or cleavage) in wild-type and woozy animals with the age of 26 weeks. Quantification of the three independent experiments is shown. The Y-axis shows fold of protein activation. The X-axis shows proteins analyzed. The letter u signifies the uncleaved or unphosphorylated status of the protein, respectively. The letter c signifies the cleaved form of a protein whereas the letter p signifies the phosphorylated form of a protein. Students unpaired t test was used. P values were as following: wt Atf6(uncleaved/cleaved) = 0.0072**; wz Atf6(uncleaved/cleaved) = 0.0105*; wt eif2α/peif2α = 0.3605; wz eif2α/peif2α = 0.0029**; wt Perk/pPerk = 0.1217; wz Perk/pPerk = 0.0387*; wt LC3(uncleaved(I)/cleaved(II)) = 0.5312; wz LC3(uncleaved(I)/cleaved(II)) = 0.4393. (PPT 516 kb)

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Roos, A., Buchkremer, S., Kollipara, L. et al. Myopathy in Marinesco–Sjögren syndrome links endoplasmic reticulum chaperone dysfunction to nuclear envelope pathology. Acta Neuropathol 127, 761–777 (2014). https://doi.org/10.1007/s00401-013-1224-4

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