Autophagy appears to play a role in the etiology and progress of misfolded
protein disorders. Although this process is dysregulated in
prion diseases, it is unknown whether this impairment is a cause or a consequence of
prion neuropathology. The study of autophagy during the progress of the disease could elucidate its role. For this purpose, we have investigated its regulation at different stages of the disease in Tg338 mice, a transgenic murine model that overexpresses the highly susceptible ovine VRQ
prion protein allele. Mice were intracerebrally inoculated with mouse-adapted classical
scrapie and euthanized at the preclinical and clinical stages of the disease. Regulation of autophagy was investigated analyzing the distribution of LC3-B and p62
proteins by immunohistochemistry. Moreover, the expression of genes involved in autophagy regulation was quantified by real-time PCR. LC3-B and p62
proteins were downregulated and upregulated, respectively, in the central nervous system of infected mice with clinical signs of
scrapie. Accumulation of p62 correlated with
scrapie-related lesions, suggesting an impairment of autophagy in highly
prion-affected areas. In addition, Gas5 (growth arrest-specific 5), Atg5 (autophagy-related 5), and Fbxw7 (F-box and WD repeat domain containing 7) transcripts were downregulated in mesencephalon and cervical spinal cord of the same group of animals. The impairment of autophagic machinery seems to be part of the pathological process of
scrapie, but only during the late stage of
prion infection. Similarities between Tg338 mice and the natural
ovine disease make them a reliable in vivo model to study
prion infection and autophagy side by side.