TY - JOUR
T1 - A rat model of human FENIB (familial encephalopathy with neuroserpin inclusion bodies)
AU - Takano, Katsura
AU - Kitao, Yasuko
AU - Inagi, Reiko
AU - Momoi, Takashi
AU - Matsuyama, Tomohiro
AU - Miyata, Toshio
AU - Yoneda, Yukio
AU - Iso, Hiroyuki
AU - Stern, David M.
AU - Hori, Osamu
AU - Ogawa, Satoshi
N1 - Funding Information:
This study is supported by Health and Labor Science Research Grants (H15-Kokoro-018). We thank N. Nishihama and M. Tamatani (Department of Neuroanatomy, Kanazawa University Medical School) for expert technical support.
PY - 2006/8/4
Y1 - 2006/8/4
N2 - 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.
AB - 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.
KW - Neuronal cell death
KW - Neuroserpin
KW - Oxidant stress
KW - Oxygen/glucose regulated protein (ORP/GRP)
KW - Protein malfolding
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U2 - 10.1016/j.bbrc.2006.06.016
DO - 10.1016/j.bbrc.2006.06.016
M3 - Article
C2 - 16782060
AN - SCOPUS:33745204166
SN - 0006-291X
VL - 346
SP - 1040
EP - 1047
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 3
ER -