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The Journal of Neuroscience, May 12, 2004, 24(19):4498-4509; doi:10.1523/JNEUROSCI.5744-03.2004

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Cellular/Molecular
The p75 Neurotrophin Receptor Can Induce Autophagy and Death of Cerebellar Purkinje Neurons

Maria L. Florez-McClure,¹ Daniel A. Linseman,¹ Charleen T. Chu,² Phil A. Barker,³ Ron J. Bouchard,¹ Shoshona S. Le,¹ Tracey A. Laessig,¹ and Kim A. Heidenreich¹

¹Department of Pharmacology, University of Colorado Health Sciences Center, and Denver Veterans Affairs Medical Center, Denver, Colorado 80262, ²Department of Pathology, Division of Neuropathology, and Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, and ³Center for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada

The cellular mechanisms underlying Purkinje neuron death in various neurodegenerative disorders of the cerebellum are poorly understood. Here we investigate an in vitro model of cerebellar neuronal death. We report that cerebellar Purkinje neurons, deprived of trophic factors, die by a form of programmed cell death distinct from the apoptotic death of neighboring granule neurons. Purkinje neuron death was characterized by excessive autophagic-lysosomal vacuolation. Autophagy and death of Purkinje neurons were inhibited by nerve growth factor (NGF) and were activated by NGF-neutralizing antibodies. Although treatment with antisense oligonucleotides to the p75 neurotrophin receptor (p75ntr) decreased basal survival of cultured cerebellar neurons, p75ntr-antisense decreased autophagy and completely inhibited death of Purkinje neurons induced by trophic factor withdrawal. Moreover, adenoviral expression of a p75ntr mutant lacking the ligand-binding domain induced vacuolation and death of Purkinje neurons. These results suggest that p75ntr is required for Purkinje neuron survival in the presence of trophic support; however, during trophic factor withdrawal, p75ntr contributes to Purkinje neuron autophagy and death. The autophagic morphology resembles that found in neurodegenerative disorders, suggesting a potential role for this pathway in neurological disease.

Key words: autophagy; Purkinje neuron; p75ntr; cell death; neurotrophin; vacuoles

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Received Dec 30, 2003; revised March 16, 2004; accepted March 17, 2004.

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