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The Journal of Neuroscience, January 24, 2007, 27(4):852-859; doi:10.1523/JNEUROSCI.4244-06.2007

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Neurobiology of Disease
N-Terminally Deleted Forms of the Prion Protein Activate Both Bax-Dependent and Bax-Independent Neurotoxic Pathways

Aimin Li,¹ Sami J. Barmada,¹ Kevin A. Roth,² and David A. Harris¹

¹Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, and ²Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294

Correspondence should be addressed to David A. Harris, Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110. Email: dharris{at}wustl.edu

Transgenic (Tg) mice expressing prion protein (PrP) with a deletion of the flexible, N-terminal tail encompassing residues 32–134 spontaneously develop ataxia, degeneration of cerebellar granule cells, and vacuolation of white matter in the brain and spinal cord, resulting in death by 3 months of age. These abnormalities are completely abrogated by coexpression of wild-type PrP from a single copy of the endogenous Prn-p gene. A similar but much more severe phenotype is seen in transgenic mice expressing PrP deleted for a conserved block of 21 amino acids (residues 105–125) within the N-terminal tail. The latter animals die within 1 week of birth in the absence of endogenous PrP, and fivefold overexpression of wild-type PrP is required to delay death beyond 1 year. To define the cellular pathways mediating the neurotoxicity of PrP32–134 and PrP105–125, we analyzed the effect of genetically deleting the proapoptotic protein Bax in mice expressing these neurotoxic forms of PrP. We find that Bax deletion in Tg(PrP32–134) mice delays the development of clinical illness and slows apoptosis of cerebellar granule cells but has no effect on white matter degeneration. In contrast, Bax deletion has no effect on the clinical or neuropathological phenotype of Tg(105–125) mice. Our results indicate that Bax-related pathways mediate the initial neurotoxic actions of PrP32–134 but that neurodegeneration induced by this protein as well as by PrP105–125 also involves Bax-independent pathways.

Key words: prion; Bax; apoptosis; transgenic; neurodegeneration; cerebellum

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Received Sept. 28, 2006; revised Dec. 9, 2006; accepted Dec. 15, 2006.

Correspondence should be addressed to David A. Harris, Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110. Email: dharris{at}wustl.edu

This article has been cited by other articles:

				R. Linden, V. R. Martins, M. A. M. Prado, M. Cammarota, I. Izquierdo, and R. R. Brentani Physiology of the Prion Protein Physiol Rev, April 1, 2008; 88(2): 673 - 728. [Abstract] [Full Text] [PDF]

				A. D. Steele, O. D. King, W. S. Jackson, C. A. Hetz, A. W. Borkowski, P. Thielen, R. Wollmann, and S. Lindquist Diminishing Apoptosis by Deletion of Bax or Overexpression of Bcl-2 Does Not Protect against Infectious Prion Toxicity In Vivo J. Neurosci., November 21, 2007; 27(47): 13022 - 13027. [Abstract] [Full Text] [PDF]

				O. Nicolas, R. Gavin, N. Braun, J. M. Urena, X. Fontana, E. Soriano, A. Aguzzi, and J. Antonio del Rio Bcl-2 overexpression delays caspase-3 activation and rescues cerebellar degeneration in prion-deficient mice that overexpress amino-terminally truncated prion FASEB J, October 1, 2007; 21(12): 3107 - 3117. [Abstract] [Full Text] [PDF]

				J. Dong, A. Li, N. Yamaguchi, S. Sakaguchi, and D. A. Harris Doppel Induces Degeneration of Cerebellar Purkinje Cells Independently of Bax Am. J. Pathol., August 1, 2007; 171(2): 599 - 607. [Abstract] [Full Text] [PDF]

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