The tumor suppressor p53 is perhaps best known as a cellular watchdog that prevents cancer by initiating apoptosis in genetically damaged cells. But might this old faithful occasionally get a little overzealous? In the July 7 Neuron, Akira Sawa and colleagues at Johns Hopkins University in Baltimore, Maryland, show that nuclear p53 associates with mutant poly-Q expanded huntingtin protein (mHtt), leading to elevated levels of p53, mitochondrial depolarization, and cell death. The authors demonstrate that inhibiting p53 rescues neurons, and that deletion of the gene suppresses HD-like phenotypes in Drosophila or mice carrying mHtt. While activation of p53 in response to stress has been recognized in several neurodegenerative diseases including Alzheimer and Parkinson diseases (reviewed in Culmsee and Mattson, 2005), Sawa’s group shows for the first time direct connections among pathological nuclear events, mitochondrial dysfunction, and p53-mediated cell death.

Picking up on multiple clues that p53 might play a role in Huntington disease pathology—p53 associates with mHtt; neurons from mHtt knock-in mice have increased p53; and p53 regulates many mitochondrial genes and genes associated with oxidative stress—first author Byoung-Il Bae and colleagues measured p53 levels and activity in neuronal cells in vitro and in brain tissue from humans and transgenic mouse models of HD. The researchers found that expression of the huntingtin protein exon 1 fragment N63-148Q in PC12 cells caused increased nuclear p53 protein levels, and that the increase depended on the presence of the pathogenic polyQ repeats. They observed increases in p53 in mHtt-transgenic mouse brains, and in brains of people with Huntington disease, but only in regions affected by the disease. They went on to show that in neurons in culture, the mHtt and p53 proteins occur in a complex, and that mHtt augments p53-stimulated transcription. When Bae and colleagues transiently transfected PC12 cells with mHtt, they found increased levels of several p53-responsive proteins that associate with mitochondria and mediate apoptotic signals. These effects were not a general response to polyQ expansions, since the polyQ form of ataxin, which causes spinal cerebral ataxia, did not have similar effects.

The regulation of mitochondrial genes and genes for oxidative stress by p53 and their augmentation by mHtt suggested that the p53 might play a role in the mitochondrial dysfunction central to HD. In agreement with this idea, they found that the p53 inhibitor, pifithrin (see ARF related news story), blocked cyanide-stimulated mitochondrial depolarization in lymphoblasts from Huntington disease patients. In PC12 cells, pifithrin prevented mitochondrial depolarization and cell death caused by expression of mHtt. When given to mice, pifithrin reversed the impairment of mitochondrial complex IV activity in the striatum of transgenic mHtt animals. Finally, using another approach to inhibit p53, Bae et al. showed that genetic deletion of p53 prevented cell death after mHtt expression in primary cortical neurons. In contrast, mHtt nuclear and cytoplasmic aggregates were not changed by p53 deletion.

To conclusively nail down p53’s central place in HD neuropathology, the researchers showed that in both fruit flies and mice transgenic for mHtt, p53 deletion decreased the severity of HD-like phenotypes. In the fly HD model, animals progressively lose retinal photoreceptors, and deletion of p53 rescues these cells. In the mouse model, crossing p53 knockouts with mHtt-Tg mice ameliorated motor dysfunction by several measures. The abnormal escape reflex seen in the transgenic mice was normalized, as was increased rotational activity, an abnormal startle reflex in response to loud noise and deficits in rotarod performance.

“By presenting such a broad portfolio of consistent experimental results, the authors made a convincing case that p53 is involved in HD disease progression,” write Albert La Spada and Richard Morrison in a preview article accompanying the work. But they point out that many questions remain about the role of p53 in HD. How is p53 upregulated by mutant Htt protein, for example?

Although Sawa and colleagues showed that p53 levels were not enhanced by the polyQ protein ataxin, it is possible that p53 could turn out to be a key player in other polyglutamine repeat diseases. Beyond the glutamine expansion diseases, La Spada and Morrison point out that Sawa’s data indicate p53 might be involved in mitochondrial dysfunction in the absence of apoptosis, a process that could lead to synaptic degeneration that occurs in many neurodegenerative diseases. As they summarize, “Clearly, additional studies will be required to fully evaluate the role of p53 in HD and other neurological disorders, since other disease proteins may find the draw of p53’s dark side impossible to resist.”

Could p53 be a clinical target for neurodegenerative disease therapy? This idea has gained some currency as observations accumulate that p53 production is rapidly increased in neurons in response to a range of insults, including DNA damage, oxidative stress, metabolic compromise, cellular calcium overload, and amyloid-β (see ARF related news story and Culmsee and Mattson review). But the downside of systemic inhibition of a tumor suppressor may be considerable, as La Spada and Morrison point out. Alternatively, targeting the specific interaction of mHtt and p53 may yield a new therapeutic approach to Huntington disease.—Pat McCaffrey


  1. 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).


    . p53 mediates cellular dysfunction and behavioral abnormalities in Huntington's disease. Neuron. 2005 Jul 7;47(1):29-41. PubMed.

    . Apoptosis in neurodegenerative disorders. Nat Rev Mol Cell Biol. 2000 Nov;1(2):120-9. PubMed.

    . 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. PubMed.

    . 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. PubMed.

    . Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Nat Med. 2003 Mar;9(3):338-42. PubMed.

    . 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. PubMed.

    . p53 in neuronal apoptosis. Biochem Biophys Res Commun. 2005 Jun 10;331(3):761-77. PubMed.

    . 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. PubMed.

    . 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. PubMed.

    . 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. PubMed.

    . 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. PubMed.

    . p53 inhibitors preserve dopamine neurons and motor function in experimental parkinsonism. Ann Neurol. 2002 Nov;52(5):597-606. PubMed.

    . The role of p53-induced apoptosis in cerebral ischemia: effects of the p53 inhibitor pifithrin alpha. Exp Neurol. 2004 Jun;187(2):478-86. PubMed.

    . Prospective therapeutic applications of p53 inhibitors. Biochem Biophys Res Commun. 2005 Jun 10;331(3):726-36. PubMed.

    . 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. PubMed.

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News Citations

  1. Toward Pinning Down p53's Role in Neurodegeneration
  2. Novel APP-p53 Interaction Found

Paper Citations

  1. . p53 in neuronal apoptosis. Biochem Biophys Res Commun. 2005 Jun 10;331(3):761-77. PubMed.

Further Reading


  1. . Intracellularly generated amyloid-beta peptide counteracts the antiapoptotic function of its precursor protein and primes proapoptotic pathways for activation by other insults in neuroblastoma cells. J Neurochem. 2004 Dec;91(6):1260-74. PubMed.
  2. . Intracellular Abeta42 activates p53 promoter: a pathway to neurodegeneration in Alzheimer's disease. FASEB J. 2005 Feb;19(2):255-7. PubMed.
  3. . The multiple roles of p53 in the pathogenesis of HIV associated dementia. Biochem Biophys Res Commun. 2005 Jun 10;331(3):799-809. PubMed.
  4. . 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. PubMed.

Primary Papers

  1. . p53 mediates cellular dysfunction and behavioral abnormalities in Huntington's disease. Neuron. 2005 Jul 7;47(1):29-41. PubMed.
  2. . The power of the dark side: Huntington's disease protein and p53 form a deadly alliance. Neuron. 2005 Jul 7;47(1):1-3. PubMed.