Dilations of the Endoplasmic Reticulum Contribute to Spongiform Degeneration and Unlock a Door to a Unified Model of Neuropathological Features in Prion Diseases

Prion diseases are fatal neurodegenerative disorders characterized by spongiform degeneration, neuronal loss, and misfolded prion protein (PrPSc) deposition. The mechanistic origins of spongiform degeneration, which manifests as intracellular vacuolation in neurons, have remained unclear. We considered similarities between the spongiform degeneration in prion diseases and vacuolation in cells exposed to cardiac glycoside (CGs) inhibitors of Na+, K+-ATPases (NKAs). Such similarities were initially described more than 50 years ago but had been dismissed because CG exposure caused vacuolation in astrocytes, not neurons. Here, we show that vacuolation shifts to neurons in mice expressing a humanized NKA α1 subunit. We further demonstrate that stressors, such as NKA α subunit overexpression and toxins triggering the unfolded protein response (UPR), cause profound ER dilation, particularly in the perinuclear space (PNS). Our pharmacological and genetic experiments implicate the transient receptor potential vanilloid 2 (TRPV2) calcium leak channel in this vacuolation process. Finally, we demonstrated that ER dilations contribute to spongiform degeneration in prion disease by directing a fluorescent marker to the lumen of these vacuoles in cryo-sectioned brains. We then explored whether this phenotype can be functionally linked to other neuropathological hallmarks observed in prion diseases. Upon surveying the neuropathological record and other distant literature niches, a model came into focus of PrPSc poisoning raft domains containing NKAs and initiating an ER-centered rescue program mediated by the UPR. We propose that this program induces sterol biosynthesis and ER hypertrophy. When paired with Ca²⁺ influx, ER dilation may be observed. Eventually, the nuclear-cytoplasmic transport of mRNAs and tRNAs will come to a halt, resulting in ribosome aggregation into paracrystalline structures, which have been widely reported in the prion literature and were often described as ‘virus-like’ particles.

Department dc:contributor.department

Laboratory Medicine and Pathobiology

Year dc:date.issued

2025

Author dc:creator

• Zhao, Wenda

Advisor dc:contributor.advisor

• Schmitt-Ulms, Gerold

• ER hypertrophy
• Inactive Ribosome
• PNS dilation
• Prion Disease
• Spongiform Degeneration
• TRPV2

Handle dc:identifier.uri

https://hdl.handle.net/1807/153308

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/153308