title: A rat model of human FENIB (familial encephalopathy with neuroserpin inclusion bodies).
abstract: FENIB (familial encephalopathy with neuroserpin inclusion bodies) is caused by intracellular accumulation/polymerization of mutant neuroserpins in the endoplasmic reticulum (ER). Transgenic rats overexpressing megsin (Tg meg), a newly identified serine protease inhibitor (serpin), demonstrated intraneuronal periodic-acid Schiff (PAS)-positive inclusions distributed throughout deeper layers of cerebral cortex, CA1 of the hippocampus, and substantia nigra. Hippocampal extracts from Tg meg rats showed increased expression of ER stress proteins, and activation of caspases-12 and -3, associated with decreased neuronal density. Enhanced ER stress was also observed in dopaminergic neurons in the substantia nigra, in parallel with decreased neuronal viability and motor coordination. In each case, PAS-positive inclusions were also positive for megsin. These data suggest that overexpression of megsin results in ER stress, eventuating in the formation of PAS-positive inclusions. Tg meg rats provide a novel model of FENIB, where accumulation of serpins in the ER induces selective dysfunction/loss of specific neuronal populations.
authors.affiliation: Department of Neuroanatomy, Kanazawa University Medical School, Ishikawa, Japan.
authors.forename: Katsura
authors.initials: K
authors.lastname: Takano
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Kitao
authors.forename: Reiko
authors.initials: R
authors.lastname: Inagi
authors.forename: Takashi
authors.initials: T
authors.lastname: Momoi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Matsuyama
authors.forename: Toshio
authors.initials: T
authors.lastname: Miyata
authors.forename: Yukio
authors.initials: Y
authors.lastname: Yoneda
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Iso
authors.forename: David M
authors.initials: DM
authors.lastname: Stern
authors.forename: Osamu
authors.initials: O
authors.lastname: Hori
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ogawa
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D016923:Cell Death; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism* / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009479:Neuropeptides / Q000378:metabolism*; D051381:Rats; D015843:Serpins / Q000378:metabolism*; D000097522:Neuroserpin
chemical_list: D009479:Neuropeptides; D015843:Serpins; D000097522:Neuroserpin; C491937:Serpinb7 protein, rat