A rat model of human FENIB (familial encephalopathy with neuroserpin inclusion bodies).
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.
Takano
Katsura
K
Department of Neuroanatomy, Kanazawa University Medical School, Ishikawa, Japan.
Kitao
Yasuko
Y
Inagi
Reiko
R
Momoi
Takashi
T
Matsuyama
Tomohiro
T
Miyata
Toshio
T
Yoneda
Yukio
Y
Iso
Hiroyuki
H
Stern
David M
DM
Hori
Osamu
O
Ogawa
Satoshi
S
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
D009479:Neuropeptides; D015843:Serpins; D000097522:Neuroserpin; C491937:Serpinb7 protein, rat