Autophagy impairment in highly prion-affected brain areas of sheep experimentally infected with atypical scrapie

Abstract Autophagy is a critical physiologic process contributing to the maintenance of cell homeostasis. Autophagy dysfunction has been directly linked to a growing number of neurodegenerative disorders, including prion diseases. However, little is known about the molecular mechanisms underlying autophagic failure and its connection with prion neuropathology. In a previous work we described alterations of this process in the central nervous system (CNS) of sheep naturally infected with classical scrapie, although specific neuronal populations such as Purkinje cells seemed to display an autophagy-related neuroprotective effect against prion toxicity. As atypical scrapie displays a lesion pattern different to the one observed in the classical form, using immunohistochemical analyses, we further investigated herein the role of autophagy in the CNS of sheep experimentally infected with atypical scrapie prions. While ATG5 protein showed a similar distribution in atypical scrapie to that observed in the classical form, expression of LC3-B and LC3-A did not change in any brain region. However, p62, a marker of impaired autophagy, was overexpressed in the most prion-affected areas, including Purkinje cells, which suggests that autophagic activity is deteriorated in the CNS of atypical scrapie and these cells are also susceptible to neurotoxicity and do not exhibit a general defensive mechanism based on autophagy. By comparing data from both clinical scrapie forms, we have demonstrated that autophagy impairment is highly dependent on the neuropathological lesion levels of the brain area analysed and may be implicated in prion neuropathology.