title: Limited Unfolded Protein Response and Inflammation in   Neuroserpinopathy.
abstract: Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a rare disease characterized by the deposition of multiple intracytoplasmic neuronal inclusions that contain mutated neuroserpin. Tg-Syracuse (Tg-Syr) mice express Ser49Pro mutated neuroserpin and develop clinical and neuropathological features of human FENIB. We used 8-, 34-, 45- and 80-week-old Tg-Syr mice to characterize neuroinflammation and the unfolded protein response (UPR) in a neurodegenerative disease in which abnormal protein aggregates accumulate within the endoplasmic reticulum (ER). There were scattered neuroserpin inclusions in Tg-Syr mice at 8 weeks of age; the numbers of neurons involved and the amount of neuroserpin per neuron increased with age throughout the CNS to 80 weeks of age; no similar inclusions were found in wild type (Tg-WT) mice at any age. Increases in numbers of astrocytes and microglia occurred at advanced disease stages. Among 22 markers in 80-week-old Tg-Syr mice, only II1b and II10rb mRNAs in the somatosensory cortex and CxCl10 and Il10rb mRNAs in the olfactory bulb were upregulated when compared with Tg-WT mice indicating a limited relationship between neuroserpin inclusions and inflammatory responses. The changes were accompanied by a transient increase in expression of Xbp1 spliced at 45 weeks and increased ERdJ4 mRNAs at 80 weeks. The sequestration of UPR activators GRP78 and GRP94 in neuroserpin inclusions might explain the limited UPR responses despite the accumulation of neuroserpin in the ER in this FENIB mouse model.
authors.forename: Irene
authors.initials: I
authors.lastname: López-González
authors.forename: Alberto
authors.initials: A
authors.lastname: Pérez-Mediavilla
authors.forename: Marta
authors.initials: M
authors.lastname: Zamarbide
authors.forename: Margarita
authors.initials: M
authors.lastname: Carmona
authors.forename: Benjamin
authors.initials: B
authors.lastname: Torrejón Escribano
authors.forename: Markus
authors.initials: M
authors.lastname: Glatzel
authors.forename: Giovanna
authors.initials: G
authors.lastname: Galliciotti
authors.forename: Isidre
authors.initials: I
authors.lastname: Ferrer
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000473:pathology; D000091342:Endoplasmic Reticulum Chaperone BiP; D004831:Epilepsies, Myoclonic / Q000235:genetics* / Q000473:pathology; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology; D009154:Mutation; D009479:Neuropeptides / Q000235:genetics* / Q000378:metabolism*; D009830:Olfactory Bulb / Q000473:pathology; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D015843:Serpins / Q000235:genetics* / Q000378:metabolism*; D016707:Tissue Fixation; D056811:Unfolded Protein Response / Q000235:genetics*; D000097522:Neuroserpin
chemical_list: D016207:Cytokines; D000091342:Endoplasmic Reticulum Chaperone BiP; D009479:Neuropeptides; D012313:RNA; D015843:Serpins; D000097522:Neuroserpin; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse