Prion diseases are a group of
neurodegenerative disorders that can be spontaneous, familial or acquired by
infection. The conversion of the
prion protein PrPC to its abnormal and misfolded
isoform PrPSc is the main event in the pathogenesis of
prion diseases of all origins. In spontaneous
prion diseases, the mechanisms that trigger the formation of PrPSc in the central nervous system remain unknown. Several reports have demonstrated that the accumulation of PrPSc can induce endoplasmic reticulum (ER) stress and
proteasome impairment from the early stages of the
prion disease. Both mechanisms lead to an increment of PrP aggregates in the secretory pathway, which could explain the pathogenesis of spontaneous
prion diseases. Here, we investigate the role of ER stress and
proteasome impairment during
prion disorders in a murine model of spontaneous
prion disease (TgVole) co-expressing the UbG76V-GFP reporter, which allows measuring the
proteasome activity in vivo. Spontaneously
prion-affected mice showed a significantly higher accumulation of the PKR-like ER
kinase (PERK), the ER chaperone binding
immunoglobulin protein (BiP/
Grp78), the ER
protein disulfide isomerase (PDI) and the UbG76V-GFP reporter than age-matched controls in certain brain areas. The upregulation of PERK, BiP, PDI and
ubiquitin was detected from the preclinical stage of the disease, indicating that ER stress and
proteasome impairment begin at early stages of the spontaneous disease. Strong correlations were found between the deposition of these markers and neuropathological markers of
prion disease in both preclinical and clinical mice. Our results suggest that both ER stress and
proteasome impairment occur during the pathogenesis of spontaneous
prion diseases.