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A slow death

Neurodegenerative diseases induce a slow form of cell death that is inconsistent with either apoptosis or necrosis. Hoshino et al. (page 589) describe a novel slow form of cell death caused by transcriptional repression, a dysfunction associated with neurons in the polyglutamine diseases.

Primary neurons grown in culture in the presence of -amanitin, a chemical repressor of transcription, survived for five days, whereas treated nonneuronal cells underwent apoptotic death within 12 hours. When the neurons finally did die, their demise did not resemble apoptosis, necrosis, or autophagy, in terms of morphology, biochemical characteristics, or DNA breakdown.

YAP, a cotranscription factor that works with p73 to induce transcription of proapoptotic genes, was highly expressed in cells undergoing this slow transcriptional repression induced atypical death (TRIAD). However, the forms of YAP protein expressed in these neurons, YAPCs, lacked the transcriptional activation domain, and thus acted as dominant-negative mutants that blocked expression of target genes.

siRNAs directed against YAPCs led to rapid death in primary neurons exposed to -amanitin, whereas overexpression of YAPCs protected nonneuronal cells from apoptosis triggers.

YAPCs were detected in neurons in brain sections from wild-type and Huntington disease model mice, and in samples from the brains of human Huntington disease patients. Relative to controls, mutant mice expressed a greater proportion of YAPCs versus full-length YAP. Moreover, overexpression of YAPCs slowed cell death in transgenic fly neurons expressing mutant huntingtin protein. Still not clear, however, is whether YAPCs slow down cell death in humans suffering from polyglutamine diseases.

Rabiya S. Tuma

rabiya{at}nasw.org

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Related Article

Transcriptional repression induces a slowly progressive atypical neuronal death associated with changes of YAP isoforms and p73

Masataka Hoshino, Mei-ling Qi, Natsue Yoshimura, Tomoyuki Miyashita, Kazuhiko Tagawa, Yo-ichi Wada, Yasushi Enokido, Shigeki Marubuchi, Phoebe Harjes, Nobutaka Arai, Kiyomitsu Oyanagi, Giovanni Blandino, Marius Sudol, Tina Rich, Ichiro Kanazawa, Erich E. Wanker, Minoru Saitoe, and Hitoshi Okazawa
J. Cell Biol. 2006 172: 589-604. [Abstract] [Full Text] [PDF]

This Article Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Tuma, R. S. Search for Related Content PubMed Articles by Tuma, R. S. Related Collections Related Article Social Bookmarking                            What's this?