**4. Conclusion**

Although the contribution of apoptosis to prion-induced death of central neurons including cerebellar ones is strongly supported, our studies of scrapie-infected PCs show that although caspase-3 is activated, the pro-apoptotic BAX/BCL-2-dependent mitochondrial pathway is not involved in the prion-induced death of these neurons. This is also the case for BSE-induced death of hippocampal and thalamic neurons [119], suggesting that prions exert neurotoxicity through BAX-independent activation of caspase-3. Ultrastructural evidence of ER stress and robust autophagy in the scrapieinfected cerebellar neurons both *in vivo* and *ex vivo* implicate them in these BAXindependent neurotoxic mechanisms. Furthermore, the autophagic blockade resulting from prion protein-deficiency in ZH-I and Ngsk *Prnp*0/0 mice may contribute to neuronal death in infectious prion-diseased cerebellar neurons. In Ngsk *Prnp*0/0 cerebellar neurons, Dpl neurotoxicity and PrP-deficiency contribute to neuronal death probably through an interplay between autophagic blockade and BAX-dependent apoptosis.

**31**

**Author details**

Audrey Ragagnin1

Nicolas Vitale1

France

Anne-Sophie Wilding1

provided the original work is properly cited.

, Qili Wang1

, Stéphane Gasman1

*Prion Proteins and Neuronal Death in the Cerebellum DOI: http://dx.doi.org/10.5772/intechopen.80701*

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

, Aurélie Guillemain1

, Nancy Grant1

1 Intracellular Membrane Trafficking in the Nervous and Neuroendocrine System,

2 In Vitro Imaging Platform, CNRS UPS 3156, University of Strasbourg, Strasbourg,

INCI, CNRS UPR3212, University of Strasbourg, Strasbourg, France

\*Address all correspondence to: byan@inci-cnrs.unistra.fr

, Siaka Dole1

and Yannick Bailly1

, Valérie Demais1,2, Cathy Royer1,2, Anne-Marie Haeberlé1

,

\*

,

*Prion Proteins and Neuronal Death in the Cerebellum DOI: http://dx.doi.org/10.5772/intechopen.80701*

*Prions - Some Physiological and Pathophysiological Aspects*

**30**

**4. Conclusion**

**Figure 18.**

Although the contribution of apoptosis to prion-induced death of central neurons including cerebellar ones is strongly supported, our studies of scrapie-infected PCs show that although caspase-3 is activated, the pro-apoptotic BAX/BCL-2-dependent mitochondrial pathway is not involved in the prion-induced death of these neurons. This is also the case for BSE-induced death of hippocampal and thalamic neurons [119], suggesting that prions exert neurotoxicity through BAX-independent activation of caspase-3. Ultrastructural evidence of ER stress and robust autophagy in the scrapieinfected cerebellar neurons both *in vivo* and *ex vivo* implicate them in these BAXindependent neurotoxic mechanisms. Furthermore, the autophagic blockade resulting from prion protein-deficiency in ZH-I and Ngsk *Prnp*0/0 mice may contribute to neuronal death in infectious prion-diseased cerebellar neurons. In Ngsk *Prnp*0/0 cerebellar neurons, Dpl neurotoxicity and PrP-deficiency contribute to neuronal death probably through an interplay between autophagic blockade and BAX-dependent apoptosis.

*Western blot of autophagic markers p62, beclin-1 and LAMP-1.* **A***. p62 and* **B***. Beclin-1. The markers were weakly expressed in WT COCS, but increased in DIV3 and DIV5 COCS from PrP-deficient mice.* **C***,* **D***. LAMP-1 did not vary in WT and ZH-1 COCS from DIV3 to DIV7, but increased in DIV7 Ngsk Prnp0/0 COCS* 

*indicating increased lysosomal activity (p < 0.05; n = 3 mice/genotype and DIV).*
