title: The unfolded protein response in models of human mutant G93A amyotrophic lateral sclerosis.
abstract: Recent studies indicate that endoplasmic reticulum (ER) stress is involved in the pathogenesis of familial and sporadic amyotrophic lateral sclerosis (ALS). ER stress occurs when the ER-mitochondria calcium cycle (ERMCC) is disturbed and misfolded proteins accumulate in the ER. To cope with ER stress, the cell engages the unfolded protein response (UPR). While activation of the UPR has been shown in some ALS models and tissues, ER stress elements have not been studied directly in motor neurons. Here we investigated the expression of XBP1 and ATF6α and phosphorylation of eIF2α, and their modulation, in mutated SOD1(G93A)  NSC34 and animal model of ALS. Expression of XBP1 and ATF6α mRNA and protein was enhanced in SOD1(G93A)  NSC34 cells. Activation of ATF6α and XBP1 and phosphorylation of eIF2α were detectable in mutated SOD1(G93A)  motor but not in wild-type motor neurons. Treatment with the ER stressor thapsigargin enhanced phosphorylation of eIF2α and activated proteolysis of ATF6α and splicing of XBP1 in NSC34 and motor neurons in a time-dependent manner. The present study thus provides direct evidence of activated UPR in motor neurons which overexpress human pathogenic mutant SOD1(G93A) , providing evidence that ER stress plays a major role in ALS.
authors.affiliation: University Hospital Jena, Hans-Berger Department of Neurology, Friedrich-Schiller University, Erlanger Allee 101, D-07747, Germany. tino.prell@med.uni-jena.de
authors.forename: T
authors.initials: T
authors.lastname: Prell
authors.forename: J
authors.initials: J
authors.lastname: Lautenschläger
authors.forename: O W
authors.initials: OW
authors.lastname: Witte
authors.forename: M T
authors.initials: MT
authors.lastname: Carri
authors.forename: J
authors.initials: J
authors.lastname: Grosskreutz
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000502:physiology*; D009924:Organ Culture Techniques; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D056811:Unfolded Protein Response / Q000502:physiology*
chemical_list: C109415:SOD1 G93A protein; D013482:Superoxide Dismutase