Published online 6 February 2006. doi:10.1083/jcb1724iti2
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 172, Number 4, 481-481
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, YAP
Cs, 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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Transcriptional repression induces a slowly progressive atypical neuronal death associated with changes of YAP isoforms and p73
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