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Bcl-2 overexpression delays caspase-3 activation and rescues cerebellar degeneration in prion-deficient mice that overexpress amino-terminally truncated prion

Oriol Nicolas^*,, Rosalina Gavín^*,, Nathalie Braun, Jesús Mariano Ureña, Xavier Fontana^*, Eduardo Soriano, Adriano Aguzzi and José Antonio del Río^*,,1

^* Cellular and Molecular Basis of Neurodegeneration and Neurorepair, Department of Cell Biology, University of Barcelona, Barcelona, Spain;

Developmental Neurobiology and Regeneration, Institute for Research in Biomedicine (IRB Barcelona), Department of Cell Biology, University of Barcelona, Barcelona, Spain; and

Institute of Neuropathology, University Hospital of Zürich, Zurich, Switzerland

¹Correspondence: Department of Cell Biology, Institute for Research in Biomedicine, University of Barcelona, Josep Samitier 1–5, E-08028 Barcelona, Spain. E-mail: jadelrio{at}pcb.ub.es, jadelrio{at}ub.edu

Prnp knockout mice that overexpress an amino-truncated form of PrPc (PrP) are ataxic and display cerebellar cell loss and premature death. Studies on the molecular and intracellular events that trigger cell death in these mutants may contribute to elucidate the functions of PrPc and to the design of treatments for prion disease. Here we examined the effects of Bcl-2 overexpression in neurons on the development of the neurological syndrome and cerebellar pathology of PrP. We show that PrP overexpression activates the stress-associated kinases ERK1–2 in reactive astroglia, p38 and the phosphorylation of p53, which leads to the death of cerebellar neurons in mutant mice. We found that the expression of PrP in cell lines expressing very low levels of PrPc strongly induces the activation of apoptotic pathways, thereby leading to caspase-3 activation and cell death, which can be prevented by coexpressing Bcl-2. Finally, we corroborate in vivo that neuronal-directed Bcl-2 overexpression in PrP mice (PrP Bcl-2) markedly reduces caspase-3 activation, glial activation, and neuronal cell death in cerebellum by improving locomotor deficits and life expectancy.—Nicolas, O., Gavín, R., Braun, N., Ureña, J. M., Fontana, X., Soriano, E., Aguzzi, A., del Río,. J. A. Bcl-2 overexpression delays caspase-3 activation and rescues cerebellar degeneration in prion-deficient mice that overexpress amino-terminally truncated prion.

Key Words: cerebellar syndrome • granule cells • oxidative damage • prion protein

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