title: Altered localization, abnormal modification and loss of function of Sigma receptor-1 in amyotrophic lateral sclerosis.
abstract: Intracellular accumulations of mutant, misfolded proteins are major pathological hallmarks of amyotrophic lateral sclerosis (ALS) and related disorders. Recently, mutations in Sigma receptor 1 (SigR1) have been found to cause a form of ALS and frontotemporal lobar degeneration (FTLD). Our goal was to pinpoint alterations and modifications of SigR1 in ALS and to determine how these changes contribute to the pathogenesis of ALS. In the present study, we found that levels of the SigR1 protein were reduced in lumbar ALS patient spinal cord. SigR1 was abnormally accumulated in enlarged C-terminals and endoplasmic reticulum (ER) structures of alpha motor neurons. These accumulations co-localized with the 20s proteasome subunit. SigR1 accumulations were also observed in SOD1 transgenic mice, cultured ALS-8 patient's fibroblasts with the P56S-VAPB mutation and in neuronal cell culture models. Along with the accumulation of SigR1 and several other proteins involved in protein quality control, severe disturbances in the unfolded protein response and impairment of protein degradation pathways were detected in the above-mentioned cell culture systems. Furthermore, shRNA knockdown of SigR1 lead to deranged calcium signaling and caused abnormalities in ER and Golgi structures in cultured NSC-34 cells. Finally, pharmacological activation of SigR1 induced the clearance of mutant protein aggregates in these cells. Our results support the notion that SigR1 is abnormally modified and contributes to the pathogenesis of ALS.
authors: Institute of Neuropathology, RWTH Aachen University and JARA Brain Translational Medicine, Pauwelsstr. 30, 52074 Aachen, Germany.
authors: J
authors: J
authors: Prause
authors: A
authors: A
authors: Goswami
authors: I
authors: I
authors: Katona
authors: A
authors: A
authors: Roos
authors: M
authors: M
authors: Schnizler
authors: E
authors: E
authors: Bushuven
authors: A
authors: A
authors: Dreier
authors: S
authors: S
authors: Buchkremer
authors: S
authors: S
authors: Johann
authors: C
authors: C
authors: Beyer
authors: M
authors: M
authors: Deschauer
authors: D
authors: D
authors: Troost
authors: J
authors: J
authors: Weis
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D020013:Calcium Signaling; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics* / Q000473:pathology; D008159:Lumbar Vertebrae / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D017510:Protein Folding; D059748:Proteolysis; D017480:Receptors, sigma / Q000235:genetics* / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics; D056811:Unfolded Protein Response; D000097605:Sigma-1 Receptor
chemical_list: D050505:Mutant Proteins; D017480:Receptors, sigma; D013482:Superoxide Dismutase; D000097605:Sigma-1 Receptor