title: Loss of function of the ALS protein SigR1 leads to ER pathology associated with defective autophagy and lipid raft disturbances.
abstract: Intracellular accumulations of altered, misfolded proteins in neuronal and other cells are pathological hallmarks shared by many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Mutations in several genes give rise to familial forms of ALS. Mutations in Sigma receptor 1 have been found to cause a juvenile form of ALS and frontotemporal lobar degeneration (FTLD). We recently described altered localization, abnormal modification and loss of function of SigR1 in sporadic ALS. In order to further elucidate the molecular mechanisms underlying SigR1-mediated alterations in sporadic and familial ALS, we extended our previous studies using neuronal SigR1 knockdown cell lines. We found that loss of SigR1 leads to abnormal ER morphology, mitochondrial abnormalities and impaired autophagic degradation. Consistent with these results, we found that endosomal trafficking of EGFR is impaired upon SigR1 knockdown. Furthermore, in SigR1-deficient cells the transport of vesicular stomatitis virus glycoprotein is inhibited, leading to the accumulation of this cargo protein in the Golgi apparatus. Moreover, depletion of SigR1 destabilized lipid rafts and associated calcium mobilization, confirming the crucial role of SigR1 in lipid raft and intracellular calcium homeostasis. Taken together, our results support the notion that loss of SigR1 function contributes to ALS pathology by causing abnormal ER morphology, lipid raft destabilization and defective endolysosomal pathways.
authors.affiliation: Institute of Neuropathology, Uniklinik RWTH Aachen and JARA Brain Translational Medicine, Pauwelsstraße 30, Aachen 52074, Germany.
authors.forename: J T
authors.initials: JT
authors.lastname: Vollrath
authors.affiliation: Institute of Biomedical Engineering and Cell Biology, RWTH Aachen University and JARA Brain Translational Medicine, Pauwelsstraße 30, Aachen 52074, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Sechi
authors.affiliation: Institute of Neuropathology, Uniklinik RWTH Aachen and JARA Brain Translational Medicine, Pauwelsstraße 30, Aachen 52074, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Dreser
authors.affiliation: Institute of Neuropathology, Uniklinik RWTH Aachen and JARA Brain Translational Medicine, Pauwelsstraße 30, Aachen 52074, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Katona
authors.affiliation: Institute of Physiology, RWTH Aachen University, Pauwelsstraße 30, Aachen 52074, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Wiemuth
authors.affiliation: Institute of Biochemistry and Molecular Biology, RWTH Aachen University, Pauwelsstraße 30, Aachen 52074, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Vervoorts
authors.affiliation: Institute of Biochemistry and Molecular Biology, RWTH Aachen University, Pauwelsstraße 30, Aachen 52074, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Dohmen
authors.affiliation: Institute of Neuropathology, Uniklinik RWTH Aachen and JARA Brain Translational Medicine, Pauwelsstraße 30, Aachen 52074, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Chandrasekar
authors.affiliation: Institute of Neuropathology, Uniklinik RWTH Aachen and JARA Brain Translational Medicine, Pauwelsstraße 30, Aachen 52074, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Prause
authors.affiliation: Institute of Neuropathology, Uniklinik RWTH Aachen and JARA Brain Translational Medicine, Pauwelsstraße 30, Aachen 52074, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Brauers
authors.affiliation: Institute of Neuropathology, Uniklinik RWTH Aachen and JARA Brain Translational Medicine, Pauwelsstraße 30, Aachen 52074, Germany.
authors.forename: C M
authors.initials: CM
authors.lastname: Jesse
authors.affiliation: Institute of Neuropathology, Uniklinik RWTH Aachen and JARA Brain Translational Medicine, Pauwelsstraße 30, Aachen 52074, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Weis
authors.affiliation: Institute of Neuropathology, Uniklinik RWTH Aachen and JARA Brain Translational Medicine, Pauwelsstraße 30, Aachen 52074, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Goswami
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001343:Autophagy; D002118:Calcium / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006056:Golgi Apparatus / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D021962:Membrane Microdomains / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D041681:NIH 3T3 Cells; D017480:Receptors, sigma / Q000235:genetics / Q000378:metabolism*; D000097605:Sigma-1 Receptor
chemical_list: D002118:Calcium; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor