Prion Protein Misfolding Affects Calcium Homeostasis and Sensitizes Cells to Endoplasmic Reticulum Stress

Abstract

Prion-related disorders (PrDs) are fatal neurodegenerative disorders characterized by progressive neuronal impairment as well as the accumulation of an abnormally folded and protease resistant form of the cellular prion protein, termed PrPRES. Altered endoplasmic reticulum (ER) homeostasis is associated with the occurrence of neurodegeneration in sporadic, infectious and familial forms of PrDs. The ER operates as a major intracellular calcium store, playing a crucial role in pathological events related to neuronal dysfunction and death. Here we investigated the possible impact of PrP misfolding on ER calcium homeostasis in infectious and familial models of PrDs. Neuro2A cells chronically infected with scrapie prions showed decreased ER-calcium content that correlated with a stronger upregulation of UPR-inducible chaperones, and a higher sensitivity to ER stress-induced cell death. Overexpression of the calcium pump SERCA stimulated calcium release and increased the neurotoxicity observed after exposure of cells to brain-derived infectious PrPRES. Furthermore, expression of PrP mutants that cause hereditary Creutzfeldt-Jakob disease or fatal familial insomnia led to accumulation of PrPRES and their partial retention at the ER, associated with a drastic decrease of ER calcium content and higher susceptibility to ER stress. Finally, similar results were observed when a transmembrane form of PrP was expressed, which is proposed as a neurotoxic intermediate. Our results suggest that alterations in calcium homeostasis and increased susceptibility to ER stress are common pathological features of both infectious and familial PrD models.

Astrocyte signaling and neurodegeneration

“…107,108 Furthermore, the ER Ca 2+ content was shown to be decreased in cells chronically infected with scrapie prions, and this correlated with a higher sensitivity to ER stress-induced cell death. 109 Since a similar reduction in the ER Ca 2+ levels were recently reported in primary neurons lacking the cellular prion protein, it was postulated that PrP C may be part of the machinery deputed to maintain the intracellular Ca 2+ homeostasis. As a consequence, the loss of its function, during disease progression, may contribute to Ca 2+ derangement and synaptic failure.…”

Prion aggregates transfer through tunneling nanotubes in endocytic vesicles

“…Prion infection is also known to increase ER stress and the unfolded protein response, 29,30 a multi-armed process that among other things causes the increased splicing of a transcription factor Xbp1. Xbp1s translocates to the nucleus where it induces the expression of genes involved in lipid biosynthesis.…”

Prion protein and its role in signal transduction

“…Notably, prions were shown to impair neuronal excitability and viability by blocking L-type voltage-sensitive calcium channels [109][110][111]. In addition, alterations in ER calcium homeostasis were registered in infectious and familial models of TSEs [112]. Although not all of the cellular events of PrP …”