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The Journal of Neuroscience, July 20, 2005, 25(29):6765-6774; doi:10.1523/JNEUROSCI.1700-05.2005

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Neurobiology of Disease
FasL (CD95L/APO-1L) Resistance of Neurons Mediated by Phosphatidylinositol 3-Kinase-Akt/Protein Kinase B-Dependent Expression of Lifeguard/Neuronal Membrane Protein 35

Christoph P. Beier,¹ Jörg Wischhusen,² Marc Gleichmann,¹ Ellen Gerhardt,^1,3 Ana Pekanovic,^1,3 Andreas Krueger,⁴ Verdon Taylor,⁵ Ueli Suter,⁵ Peter H. Krammer,⁴ Matthias Endres,⁶ Michael Weller,² and Jörg B. Schulz^1,3

Laboratories of ¹Neurodegeneration and ²Molecular Neurooncology, Department of Neurology, Medical School, University of Tübingen, 72076 Tübingen, Germany, ³Department of Neurodegeneration and Restorative Research, Center of Molecular Physiology of the Brain and Center of Neurological Medicine, University of Göttingen, 37073 Göttingen, Germany, ⁴Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany, ⁵Institute of Cell Biology, Department of Biology, Eidgenössische Technische Hochschule, 8093 Zürich, Switzerland, and ⁶Department of Neurology, Charité, Humboldt University, 10117 Berlin, Germany

The contribution of Fas (CD95/APO-1) to cell death mechanisms of differentiated neurons is controversially discussed. Rat cerebellar granule neurons (CGNs) express high levels of Fas in vitro but are resistant to FasL (CD95L/APO-1L/CD178)-induced apoptosis. We here show that this resistance was mediated by a phosphatidylinositol 3-kinase (PI 3-kinase)-Akt/protein kinase B (PKB)-dependent expression of lifeguard (LFG)/neuronal membrane protein 35. Reduction of endogenous LFG expression by antisense oligonucleotides or small interfering RNA lead to increased sensitivity of CGNs to FasL-induced cell death and caspase-8 cleavage. The inhibition of PI 3-kinase activity sensitized CGNs to FasL-induced caspase-8 and caspase-3 processing and caspase-dependent fodrin cleavage. Pharmacological inhibition of PI 3-kinase, overexpression of the inhibitory protein IB, or cotransfection of an LFG reporter plasmid with dominant-negative Akt/PKB inhibited LFG reporter activity, whereas overexpression of constitutively active Akt/PKB increased LFG reporter activity. Overexpression of LFG in CGNs interfered with the sensitization to FasL by PI 3-kinase inhibitors. In contrast to CGNs, 12 glioma cell lines, which are sensitive to FasL, did not express LFG. Gene transfer of LFG into these FasL-susceptible glioma cells protected against FasL-induced apoptosis. These results demonstrate that LFG mediated the FasL resistance of CGNs and that, under certain circumstances, e.g., inhibition of the PI 3-kinase-Akt/PKB pathway, CGNs were sensitized to FasL.

Key words: apoptosis; Fas/CD95; lifeguard; cerebellar granule neurons; PI 3-kinase/Akt; caspase

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Received Dec 30, 2004; revised June 1, 2005; accepted June 1, 2005.

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