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Cellular Signature of SIL1 Depletion: Disease Pathogenesis due to Alterations in Protein Composition Beyond the ER Machinery

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Abstract

SIL1 acts as nucleotide exchange factor for the endoplasmic reticulum chaperone BiP. Mutations of SIL1 cause Marinesco-Sjögren syndrome (MSS), a neurodegenerative disorder. Moreover, a particular function of SIL1 for etiopathology of amyotrophic lateral sclerosis (ALS) was highlighted, thus declaring the functional SIL1-BiP complex as a modifier for neurodegenerative disorders. Thereby, depletion of SIL1 was associated with an earlier manifestation and in strengthened disease progression in ALS. Owing to the absence of appropriate in vitro models, the precise cellular pathophysiological mechanisms leading to neurodegeneration in MSS and triggering the same in further disorders like ALS are still elusive. We found that SIL1 depletion in human embryonic kidney 293 (HEK293) cells led to structural changes of the endoplasmic reticulum (ER) including the nuclear envelope and mitochondrial degeneration that closely mimic pathological alterations in MSS and ALS. Functional studies revealed disturbed protein transport, cytotoxicity with reduced proliferation and viability, accompanied by activation of cellular defense mechanisms including the unfolded protein response, ER-associated degradation pathway, proteolysis, and expression of apoptotic and survival factors. Our data moreover indicated that proteins involved in cytoskeletal organization, vesicular transport, mitochondrial function, and neurological processes contribute to SIL1 pathophysiology. Altered protein expression upon SIL1 depletion in vitro could be confirmed in Sil1-deficient motoneurones for paradigmatic proteins belonging to different functional classes. Our results demonstrate that SIL1-depleted HEK293 cells are an appropriate model to identify proteins modulated by SIL1 expression level and contributing to neurodegeneration in MSS and further disorders like ALS. Thereby, our combined results point out that proteins beyond such involved ER-related protein processing are affected by SIL1 depletion.

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Acknowledgments

We thank Hannelore Mader, Astrid Knischewski, and Claudia Krude for expert technical assistance. This work was supported by a grant from the 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 Interdisziplinäres Zentrum für Klinische Forschung (IZKF) Aachen (N7-4, to J.W.), by the Ministerium für Innovation, Wissenschaft und Forschung des Landes Nordrhein-Westfalen, and by the German Research Foundation (DFG; ZA 639/1-1).

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

      Andreas Roos, Stephan Buchkremer, Thomas Labisch, Eva Brauers, Christian Gatz, Chris Lentz, José Gerardo-Nava & Joachim Weis

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

      Andreas Roos, Laxmikanth Kollipara & René P. Zahedi

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    Correspondence to Andreas Roos.

    Additional information

    Laxmikanth Kollipara and Stephan Buchkremer contributed equally to this work.

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    Roos, A., Kollipara, L., Buchkremer, S. et al. Cellular Signature of SIL1 Depletion: Disease Pathogenesis due to Alterations in Protein Composition Beyond the ER Machinery. Mol Neurobiol 53, 5527–5541 (2016). https://doi.org/10.1007/s12035-015-9456-z

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