Bae BI, Xu H, Igarashi S, Fujimuro M, Agrawal N, Taya Y, Hayward SD, Moran TH, Montell C, Ross CA, Snyder SH, Sawa A.
p53 mediates cellular dysfunction and behavioral abnormalities in Huntington's disease.
Neuron. 2005 Jul 7;47(1):29-41.
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Bae et al. present compelling evidence for a crucial role of p53, a protein well-known for its role in programmed cell death, in the cellular dysfunction and associated motor abnormalities in Huntington disease (HD) (1). They establish an association between increased levels of p53, and its binding to and activation by mutant huntingtin proteins in the death of neurons in the brains of HD patients and “HD mice.” A necessary role for p53 in the disease process is suggested by amelioration of the neurodegenerative process in HD mice lacking p53 and in HD mice treated with a chemical inhibitor of p53 called pifithrin-α (PFT-α, 2-imino-2,3,4,5,6,7-hexahydrobenzothiazole). Likewise, p53 depletion or pharmacological inactivation ameliorated the observed neurobehavioral anomalies of the HD mice. Additional experiments provided evidence that p53 is an important trigger of mitochondrial dysfunction and associated oxidative stress and metabolic impairment in HD (1).
HD is one of nine different inherited polyQ disorders that are distinguished by the synthesis of different aberrantly folded proteins that exert their toxicity by perturbing signaling and metabolic pathways. The interaction between mutant huntingtin and p53 may be unique amongst the polyQ diseases, as p53 did not interact with polyQ-expanded ataxin-1 (1). Nevertheless, there is a growing body of evidence suggesting a role for p53 in the dysfunction and death of neurons that occur in several different neurodegenerative disorders including Alzheimer disease (AD), Parkinson disease (PD), stroke, and head trauma (2-6). Although initiated by different environmental and/or genetic factors, p53 may contribute to mitochondrial impairment, cellular dysfunction, and neuronal death in each disorder.
There are at least two mechanisms by which p53 can trigger apoptosis. First, acting as a transcription factor, it rapidly upregulates the expression of Bax and related proapoptotic members of the Bcl-2 family of proteins (7). Bax then binds to the membrane of mitochondria, which increases the permeability of the mitochondrial membrane, resulting in the release of cytochrome c, apoptosis-inducing factor, and other molecules that activate proteases and DNAases that destroy the cell. Second, p53 may directly interact with mitochondrial membranes and/or facilitate translocation of Bax to the mitochondrial membrane (8). Both mechanisms may be operative in neurons, with the latter mechanism playing a role in local dysfunction and degeneration of synapses (9).
By expanding on the 2-imino-2,3,4,5,6,7-hexahydrobenzothiazole pharmacophore, we have developed yet more potent p53 inactivators (10) and have documented their ability to protect neurons against dysfunction and death in cell culture and animal models of stroke, PD, and AD (10-13). These and similar agents are proving to be valuable pharmacological tools in defining mechanisms underpinning cellular dysfunction and determining the point when neurons become irreversibly committed to die to define a window of therapeutic opportunity. In addition, because they are potent and effective in protecting neurons in the brain when administered systemically, p53 inhibitors could potentially slow or halt processes that gradually render neurons dysfunctional in a wide number of debilitating neurodegenerative diseases. Gudkov and Komorov, who originally demonstrated the specificity and potency of PFTα as a p53 inhibitor, have since generated related small molecule inhibitors of p53 which are effective in reducing tissue damage in models of chemo- and radiotherapy (14). However, because p53 normally plays an important role in eliminating cells with mutations, potential side effects of p53 inhibitors in proliferative tissues must be established before these agents can be used in humans (14,15).