Abstract
Autophagy is a dynamic cellular mechanism involved in protein and organelle turnover through lysosomal degradation. Autophagy regulation modulates the pathologies associated with many neurodegenerative diseases. Using sheep naturally infected with scrapie as a natural animal model of prion diseases, we investigated the regulation of autophagy in the central nervous system (CNS) during the clinical phase of the disease. We present a gene expression and protein distribution analysis of different autophagy-related markers and investigate their relationship with prion-associated lesions in several areas of the CNS. Gene expression of autophagy markers ATG5 and ATG9 was downregulated in some areas of scrapie brains. In contrast, ATG5 protein accumulates in medulla oblongata and positively correlates with prion deposition and scrapie-related lesions. The accumulation of this protein and p62, a marker of autophagy impairment, suggests that autophagy is decreased in the late phases of the disease. However, the increment of LC3 proteins and the mild expression of p62 in basal ganglia and cerebellum, primarily in Purkinje cells, suggests that autophagy machinery is still intact in less affected areas. We hypothesize that specific cell populations of the CNS may display neuroprotective mechanisms against prion-induced toxicity through the induction of PrPSc clearance by autophagy.
Highlights
Transmissible spongiform encephalopathies (TSEs), or prion diseases, are a group of fatal neurodegenerative disorders that can affect humans and animals[1]
PrPSc immunolabelling was significantly strong in P, T and medulla oblongata (Mo), moderate in Cbl and frontal cortex (Fc), and weak in basal ganglia (Bg), basal ganglia cortex (Bgc) and thalamic cortex (Tc)
Prion diseases are a group of neurodegenerative disorders characterized by accumulation of a proteinase resistant form of the prion protein (PrPSc) in the central nervous system (CNS), which leads to spongiform degeneration and ultimate neuronal death
Summary
Transmissible spongiform encephalopathies (TSEs), or prion diseases, are a group of fatal neurodegenerative disorders that can affect humans and animals[1]. One of the primary roles of autophagy is to respond to nutrient starvation by producing amino acids[10] Besides this fundamental role, autophagy contributes to other physiological processes such as intracellular clearance, differentiation, organismal development and elimination of invading pathogens[10,11]. Autophagy contributes to other physiological processes such as intracellular clearance, differentiation, organismal development and elimination of invading pathogens[10,11] Despite these pro-survival functions, autophagy can mediate a non-apoptotic cell death, called autophagic cell death[12]. The biological role of autophagy in the natural disease, or even the relationship of this process with prion-related pathology, are still poorly understood Investigating this process in natural models such as ovine scrapie could possibly help in understanding the role of autophagy in human prion diseases, as studies on human brain samples are very few and generally suffer from small number of replicates[20]
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