Reduced phosphatases and hyperphosphorylated glutamatergic receptors persist from early to late stages of prion disease
Year: 2026
Type: preprint
Abstract: Synapse loss occurs early in prion disease, yet the intracellular signaling driving this dysregulation remains poorly understood. Evidence of neuronal hyperactivity was reported in humans with sporadic and familial CJD as well as in the early stages of prion disease in mice (strain 22L). Here we perform a time course study of prion-infected mice (strain RML) and show an increase in the immediate-early gene, Arc , suggesting this is a conserved response to prions. We also observed a persistent decrease in phosphatase abundance (PP1α and PP2B) in the cerebral cortex starting at the earliest timepoint (preclinical). At this stage, mGluR5 dimers and phosphorylated AMPA receptors were increased. By clinical disease onset, mGluR5 dimers declined and activity shifted toward NMDA receptor activation, marked by GluN2B hyperphosphorylation. Together, these findings suggest that early phosphatase reduction accompanies neuronal hyperactivity, and precedes substantial inflammation. Elucidating the mechanisms driving this early phosphatase loss and its role in neuronal hyperactivity may reveal novel therapeutic targets for prion disease. Significance statement Synapse loss and neuronal hyperactivity are early features of prion and Alzheimer’s disease (AD), yet the underlying molecular drivers remain poorly understood. In the current time course study, we reveal elevated levels of neuronal activity protein, Arc, at early, mid, and late timepoints of prion disease. Concurrently, we reveal a persistent and early reduction in key phosphatases (PP1α and PP2B). Additionally, we observed hyperphosphorylation of glutamatergic receptors starting from subclinical stages, before overt neuroinflammation or neuronal loss occur. Furthermore, we uncover a disease-stage-dependent transition from early AMPAR/mGluR5 alterations to late-stage NMDAR involvement. Understanding the mechanisms driving early phosphatase loss and neuronal hyperactivity could reveal novel therapeutic targets for prion disease.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7222452111