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. Author manuscript; available in PMC: 2010 Jul 29.
Published in final edited form as: Neuron. 2008 Dec 10;60(5):803–817. doi: 10.1016/j.neuron.2008.10.015

Figure 7. Schematic model.

Figure 7

Proposed model for p25-mediated cell death involving inhibition of HDAC1 activity which leads to DNA double-strand breaks and aberrant cell cycle activity. Neurotoxic stimuli such as ischemia results in p25 accumulation. This accumulation results in interaction with and inhibition of multiple aspects of HDAC1 activity, as shown in Figure 4, in a manner that is dependent on Cdk5, as shown in Figure 4E. Inhibition of HDAC1 results in DNA damage and aberrant expression of cell cycle genes which is likely associated with local histone deacetylation (Figure 5, Figure 4G, Figure S7), and which ultimately leads to neuronal death (Figure 3). The neurotoxic effects of p25 accumulation and downstream effects appear to be reversible before a certain period of induction (Figure 3C). The circle labeled ‘N’ represents nucleosome, while ‘A’ represents acetylation of histone tails. The nucleosomes with ‘A’ represent acetylated nucleosomes and open chromatin loci, while nucleosome on far right represents a deacetylated nucleosome and closed chromatin locus.