Nature Genetics
26, 29 - 36 (2000)
doi:10.1038/79139
Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcriptionTakayoshi Shimohata1, Toshihiro Nakajima3, Mitsunori Yamada2, Chiharu Uchida4, Osamu Onodera1, Satoshi Naruse1, Tetsuya Kimura1, Reiji Koide1, Kenkichi Nozaki1, Yasuteru Sano1, Hiroshi Ishiguro5, Kumi Sakoe6, Takayuki Ooshima3, Aki Sato1, Takeshi Ikeuchi1, Mutsuo Oyake1, Toshiya Sato1, Yasuyuki Aoyagi1, Isao Hozumi1, Toshiharu Nagatsu5, Yoshihisa Takiyama6, Masatoyo Nishizawa6, Jun Goto7, Ichiro Kanazawa7, Irwin Davidson8, Naoko Tanese9, Hitoshi Takahashi2
& Shoji Tsuji11
Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan. 2
Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan. 3
Institute of Applied Biochemistry, TARA Center, University of Tsukuba, Ibaraki, and PRESTO JST, Institute of Medical Science, St. Marianna University of Medicine, Kawasaki, Japan. 4
Department of Biochemistry, Hamamatsu University School of Medicine, Shizuoka, Japan. 5
Institute for Comprehensive Medical Science, Fujita Health University, Aichi, Japan. 6
Department of Neurology, Jichi Medical School, Tochigi, Japan. 7
Department of Neurology, Institute for Brain Research, Faculty of Medicine, University of Tokyo, Tokyo, Japan. 8
Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS/INSERM/ULP, France. 9
Department of Microbiology and Kaplan Comprehensive Cancer Center, New York University Medical Center, New York, USA.
Correspondence should be addressed to Shoji Tsuji tsuji@cc.niigaa-u.ac.jpAt least eight inherited neurodegenerative diseases are caused by expanded CAG repeats encoding polyglutamine (polyQ) stretches. Although cytotoxicities of expanded polyQ stretches are implicated, the molecular mechanisms of neurodegeneration remain unclear. We found that expanded polyQ stretches preferentially bind to TAFII130, a coactivator involved in cAMP-responsive element binding protein (CREB)-dependent transcriptional activation, and strongly suppress CREB-dependent transcriptional activation. The suppression of CREB-dependent transcription and the cell death induced by polyQ stretches were restored by the co-expression of TAFII130. Our results indicate that interference of transcription by the binding of TAFII130 with expanded polyQ stretches is involved in the pathogenetic mechanisms underlying neurodegeneration.
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