Artikel
ALS linked mutant Sigma receptor-1(E102Q) leads to disrupted RNA processing and ER stress mediated defects in protein homeostasis
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Autoren
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A. Dreser
- Institute of Neuropathology, Uniklinik RWTH, Aachen, Germany
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J. T. Vollrath
- Institute of Neuropathology, Uniklinik RWTH, Aachen, Germany
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A. Sechi
- Institute of Biomedical Engineering and Cell Biology, RWTH University, Aachen, Germany
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A. Yamoah
- Institute of Neuropathology, Uniklinik RWTH, Aachen, Germany
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A. Roos
- Institute of Neuropathology, Uniklinik RWTH, Aachen, Germany
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I. Katona
- Institute of Neuropathology, Uniklinik RWTH, Aachen, Germany
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S. Bohlega
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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A. Al-Saif
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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D. Wiemuth
- Institute of Physiology, RWTH Aachen University, Aachen, Germany
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Y. Tian
- Institute of Physiology, RWTH Aachen University, Aachen, Germany
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J. Vervoorts
- Institute of Biochemistry and Molecular Biology, RWTH University, Aachen, Germany
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M. Dohmen
- Institute of Biochemistry and Molecular Biology, RWTH University, Aachen, Germany
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J. Aninik
- Division of Neuropathology, Department of Pathology, Academic Medical Centre, Amsterdam, Netherlands
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D. Troost
- Division of Neuropathology, Department of Pathology, Academic Medical Centre, Amsterdam, Netherlands
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J. Weis
- Institute of Neuropathology, Uniklinik RWTH, Aachen, Germany
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A. Goswami
- Institute of Neuropathology, Uniklinik RWTH, Aachen, Germany
| Veröffentlicht: | 25. August 2015 |
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Gliederung
Text
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective degeneration of upper and lower motor neurons and their target muscles. Mutant misfolded proteins, which often form intracellular inclusion bodies, are pathological hallmarks of both sporadic and familial forms of ALS. The disruption of the functional interplay between protein degradation processes like autophagy and RNA processing has been proposed as an integrated model that potentially merges several ALS-FTD associated genes into a common pathological pathway. A recently discovered point mutation (E102Q) in the Sigma receptor 1 (SigR1) gene has been identified to cause juvenile ALS and frontotemporal lobar dementia (FTLD). However, the underlying mechanisms how this E102Q mutation contributes to ALS pathogenesis have not been unravelled so far. In our previous study, we described autophagy impairment and the neuropathological consequences due to a loss of SigR1 protein in neuronal cell lines.
In order to extend our knowledge from previous findings, the present study is aimed to investigate the molecular mechanism(s) underlying the mutant SigR1 (mSigR1) induced neurotoxicity.
We found that the mSigR1 protein is highly unstable and accumulates in the endoplasmic reticulum (ER), where it compromises the ER structure as well as ER related functions and further induces ER stress mediated cellular toxicity. Moreover, the over-expression of mSigR1 in cell lines lacking endogenous SigR1 results in a disturbed calcium homeostasis and impaired autophagic degradation. As a consequence of an altered ER-Golgi structure upon mSigR1 expression, we found that vesicular trafficking and endolysosomal pathways are also disturbed in mSigR1 expressing cells. Remarkably, the expression of mSigR1 leads to mislocalization of RNA binding proteins like Matrin 3 (MATR3) and pTDP43 and association within the stress granules (SGs). These findings were finally confirmed in primary lymphoblasts derived from ALS patients harbouring the E102Q mutation in SigR1. Taken together, our data demonstrate that the contribution of mSigR1 to ALS pathogenesis comprises a vicious circle involving ER stress, disturbed RNA metabolism, deranged calcium homeostasis and defective endolysosomal pathways.
