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).
References:
1. 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. Abstract
2. Mattson MP. Apoptosis in neurodegenerative disorders.
Nat Rev Mol Cell Biol. 2000 Nov;1(2):120-9. Review. Abstract
3. Zhang Y, McLaughlin R, Goodyer C, LeBlanc A. Selective cytotoxicity of intracellular amyloid beta peptide1-42 through p53 and Bax in cultured primary human neurons.
J Cell Biol. 2002 Feb 4;156(3):519-29. Epub 2002 Jan 28. Abstract
4. Alves Da Costa C, Paitel E, Vincent B, Checler F. Alpha-synuclein lowers p53-dependent apoptotic response of neuronal cells. Abolishment by 6-hydroxydopamine and implication for Parkinson's disease. J Biol Chem. 2002 Dec 27;277(52):50980-4. Epub 2002 Oct 22. Abstract
5. Cheng T, Liu D, Griffin JH, Fernandez JA, Castellino F, Rosen ED, Fukudome K, Zlokovic BV. Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Nat Med. 2003 Mar;9(3):338-42. Epub 2003 Feb 3. Abstract
6. Napieralski JA, Raghupathi R, McIntosh TK. The tumor-suppressor gene, p53, is induced in injured brain regions following experimental traumatic brain injury. Brain Res Mol Brain Res. 1999 Jul 23;71(1):78-86. Abstract
7. Culmsee C, Mattson MP. p53 in neuronal apoptosis. Biochem Biophys Res Commun. 2005 Jun 10;331(3):761-77. Review. Abstract
8. Erster S, Mihara M, Kim RH, Petrenko O, Moll UM. In vivo mitochondrial p53 translocation triggers a rapid first wave of cell death in response to DNA damage that can precede p53 target gene activation. Mol Cell Biol. 2004 Aug;24(15):6728-41. Abstract
9. Gilman CP, Chan SL, Guo Z, Zhu X, Greig N, Mattson MP. p53 is present in synapses where it mediates mitochondrial dysfunction and synaptic degeneration in response to DNA damage, and oxidative and excitotoxic insults. Neuromolecular Med. 2003;3(3):159-72. Abstract
10. Zhu X, Yu QS, Cutler RG, Culmsee CW, Holloway HW, Lahiri DK, Mattson MP, Greig NH. Novel p53 inactivators with neuroprotective action: syntheses and pharmacological evaluation of 2-imino-2,3,4,5,6,7-hexahydrobenzothiazole and 2-imino-2,3,4,5,6,7-hexahydrobenzoxazole derivatives. J Med Chem. 2002 Nov 7;45(23):5090-7. Abstract
11. Culmsee C, Zhu X, Yu QS, Chan SL, Camandola S, Guo Z, Greig NH, Mattson MP. A synthetic inhibitor of p53 protects neurons against death induced by ischemic and excitotoxic insults, and amyloid beta-peptide. J Neurochem. 2001 Apr;77(1):220-8. Abstract
12. Duan W, Zhu X, Ladenheim B, Yu QS, Guo Z, Oyler J, Cutler RG, Cadet JL, Greig NH, Mattson MP. p53 inhibitors preserve dopamine neurons and motor function in experimental parkinsonism. Ann Neurol. 2002 Nov;52(5):597-606. Abstract
13. Leker RR, Aharonowiz M, Greig NH, Ovadia H. The role of p53-induced apoptosis in cerebral ischemia: effects of the p53 inhibitor pifithrin alpha. Exp Neurol. 2004 Jun;187(2):478-86. Abstract
14. Gudkov AV, Komarova EA. Prospective therapeutic applications of p53 inhibitors.
Biochem Biophys Res Commun. 2005 Jun 10;331(3):726-36. Review. Abstract
15. Greig NH, Mattson MP, Perry T, Chan SL, Giordano T, Sambamurti K, Rogers JT, Ovadia H, Lahiri DK. New Therapeutic Strategies and Drug Candidates for Neurodegenerative Diseases: p53 and TNF-{alpha} Inhibitors, and GLP-1 Receptor Agonists.
Ann N Y Acad Sci. 2004 Dec;1035:290-315. Abstract
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