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Human Molecular Genetics, 2002, Vol. 11, No. 13 1505-1515
© 2002 Oxford University Press

Polyglutamine aggregates stimulate ER stress signals and caspase-12 activation

Yoriko Kouroku1, Eriko Fujita1, Atsushi Jimbo1, Tateki Kikuchi2, Takanori Yamagata3, Mariko Y. Momoi3, Eiki Kominami4, Keisuke Kuida5, Kazuhiro Sakamaki6, Shin Yonehara6 and Takashi Momoi1,*

1Division of Development and Differentiation and 2Division of Animal Models for Human Disease, National Institute of Neuroscience, 4-1-1 Ogawahigashi-machi, Kodaira, Tokyo 187-8502, Japan, 3Department of Pediatrics, Jichi Medical School, Yakushiji, Minamikawachi-machi, Kawachi-gun, Tochigi 329-0498, Japan, 4Department of Biochemistry, Juntendo University School of Medicine, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan, 5Molecular Biology Vertex Pharmaceuticals, 130 Waverly Street, Cambridge, MA 02139-4242, USA and 6Graduate School of Biostudies, Kyoto University, Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan

Received January 31, 2002; Accepted April 19, 2002

Accumulation of unfolded and malfolded proteins causes endoplasmic reticulum (ER) stress, stimulating unfolded protein response (UPR) and c-Jun N-terminal kinase (JNK) activation and activating caspase-12 located on the ER. Little is known about the relationship between the ER stress and polyglutamine [poly(Q)] aggregates. Poly(Q)72 repeats [poly(Q)72] induced the stimulation of ER stress signals such as JNK activation, upregulation of Grp78/Bip and caspase-12 activation in C2C5 cells. We prepared antiserum against the cleavage site of mouse caspase-12 at D318 (anti-m12D318), and showed that poly(Q)72 with perinuclear aggregates, cytoplasmic inclusions and nuclear inclusions stimulated JNK activation and anti-m12D318 immunoreactivity, but poly(Q)72 with dispersed aggregates and small nuclear aggregates showed a significantly less effect. Poly(Q)72 and poly(Q)11 dispersed in cytoplasm did not. Anti-m12D318-positive cells showed apoptotic features. Unlike anti-m8D387 immunoreactivity, the anti-m12D318 immunoreactivity was not coaggregated with poly(Q). Ac-IETD-fmk (caspase-8 inhibitor) and Ac-DEVD-CHO (caspase-3 inhibitor) did not prevent the anti-m12D318 immunoreactivity induced by poly(Q)72 aggregates. Anti-m12D318 immunoreactivity was detected in caspase-8-/- and caspase-3-/- mouse embryonic fibroblasts expressing poly(Q)72 aggregates. Thus, caspase-12 was activated by poly(Q)72 aggregates via a pathway independent of caspase-8 and caspase-3 activation, and caspase-12 activation was closely associated with poly(Q) aggregate-mediated cell death. Stimulation of ER stress signals may be involved in the pathogenesis of neurodegenerative disorders with poly(Q) expansion.

* To whom correspondence should be addressed. Tel: +81 42 3412711; Fax: +81 42 3461754; Email: momoi{at}ncnp.go.jp


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