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Neurobiol Dis. 2019 Apr;124:218-229. doi: 10.1016/j.nbd.2018.11.019. Epub 2018 Nov 20.

SIL1 deficiency causes degenerative changes of peripheral nerves and neuromuscular junctions in fish, mice and human.

Author information

1
Leibniz-Institut für Analytische Wissenschaften, ISAS, e.V. Dortmund, 44227, Dortmund, Germany. Electronic address: vietxuan.phan@isas.de.
2
MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK. Electronic address: dan.cox@nnewcastle.ac.uk.
3
MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK; Department of Neuromotor and Biomedical Sciences, Pathology Unit, University of Bologna, Bologna, Italy. Electronic address: silvia.cipriani5@studio.unibo.it.
4
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada; Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa, Canada. Electronic address: SSpendiff@cheo.on.ca.
5
Institute of Neuropathology, University Hospital RWTH Aachen, Aachen, 52074, Germany. Electronic address: sbuchkremer@ukacchen.de.
6
MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK. Electronic address: emily.o'connor@newcastle.ac.uk.
7
Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK. Electronic address: rita.horvath@doctors.org.uk.
8
Department of Neuropathology, Charité Berlin, Germany. Electronic address: hans-hilmar.goebel@charite.de.
9
Leibniz-Institut für Analytische Wissenschaften, ISAS, e.V. Dortmund, 44227, Dortmund, Germany. Electronic address: denisa.hathazi@isas.de.
10
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada; Department of Neuropediatrics and Muscle Disorders, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany; Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa, Canada.
11
Institute of Molecular and Cell Biology, Mannheim University of Applied Sciences, Mannheim, Germany; Interdisciplinary Center for Neurosciences, Heidelberg University, Heidelberg, Germany; Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany. Electronic address: t.straka@hs-mannheim.de.
12
Institute of Molecular and Cell Biology, Mannheim University of Applied Sciences, Mannheim, Germany; Interdisciplinary Center for Neurosciences, Heidelberg University, Heidelberg, Germany; Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany. Electronic address: r.rudolf@hs-mannheim.de.
13
Institute of Neuropathology, University Hospital RWTH Aachen, Aachen, 52074, Germany. Electronic address: jweis@ukaachen.de.
14
Leibniz-Institut für Analytische Wissenschaften, ISAS, e.V. Dortmund, 44227, Dortmund, Germany; Institute of Neuropathology, University Hospital RWTH Aachen, Aachen, 52074, Germany; Pediatric Neurology, University Childrens Hospital, University of Duisburg-Essen, Faculty of Medicine, Essen, Germany. Electronic address: andreas.roos@isas.de.

Abstract

BACKGROUND:

Marinesco-Sjögren Syndrome (MSS) is a rare neuromuscular condition caused by recessive mutations in the SIL1 gene resulting in the absence of functional SIL1 protein, a co-chaperone for the major ER chaperone, BiP. As BiP is decisive for proper protein processing, loss of SIL1 results in the accumulation of misshaped proteins. This accumulation likely damages and destroys cells in vulnerable tissues, leading to congenital cataracts, cerebellar ataxia, vacuolar myopathy and other MSS phenotypes. Whether the peripheral nervous system (PNS) is affected in MSS has not been conclusively shown.

METHODS:

To study PNS vulnerability in MSS, intramuscular nerves fibres from MSS patients and from SIL1-deficient mice (woozy) as well as sciatic nerves and neuromuscular junctions (NMJ) from these mice have been investigated via transmission electron microscopic and immunofluorescence studies accompanied by transcript studies and unbiased proteomic profiling. In addition, PNS and NMJ integrity were analyzed via immunofluorescence studies in an MSS-zebrafish model which has been generated for that purpose.

RESULTS:

Electron microscopy revealed morphological changes indicative of impaired autophagy and mitochondrial maintenance in distal axons and in Schwann cells. Moreover, changes of the morphology of NMJs as well as of transcripts encoding proteins important for NMJ function were detected in woozy mice. These findings were in line with a grossly abnormal structure of NMJs in SIL1-deficient zebrafish embryos. Proteome profiling of sciatic nerve specimens from woozy mice revealed altered levels of proteins implicated in neuronal maintenance suggesting the activation of compensatory mechanisms.

CONCLUSION:

Taken together, our combined data expand the spectrum of tissues affected by SIL1-loss and suggest that impaired neuromuscular transmission might be part of MSS pathophysiology.

KEYWORDS:

Marinesco-Sjögren syndrome; Neuromuscular junction; PNS pathology; SIL1; Woozy

PMID:
30468864
DOI:
10.1016/j.nbd.2018.11.019

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