Neuronal, but not astrocytic or microglial, Hrs depletion accelerates prion disease progression. A, Schematic illustrates the timeline of disease progression for prion-inoculated mice. Days to average onset of terminal prion disease are shown. Created with biorender.com. B, C, Survival curves of Hrs^f/fGFAP-Cre (B) and Hrs^f/fLysM-Cre (C) intracerebrally inoculated with prions (gray line shows uninfected Cre+ control mice). D, E, Representative Western blottings and quantification of PK-resistant PrP^Sc in brain lysates (n = 8-9 GFAP-Cre mice/group; n = 6–11 LysM-Cre mice/group). F, G, Brain sections immunolabeled for PrP show diffuse PrP^Sc deposits in the hippocampus (CA1). H–J, Survival curves, representative Western blottings and quantification of PrP^Sc, and PrP-immunolabeled hippocampal sections from prion-inoculated Hrs^f/fSyn1-Cre mice (n = 7–8 Syn1-Cre mice/group). K, Western blottings and quantification of PrP^Sc in PK-digested brain lysates from Hrs^f/fSyn1-Cre⁻ and Cre⁺ mice collected at 107 dpi (n = 4–5 mice/group). L, Brain sections immunolabeled for PrP show similar diffuse PrP^Sc deposits in the cerebral cortex. M, Western blottings and quantification of PrP^Sc in NaPTA-precipitated, PK-digested brain lysates from Hrs^f/fSyn1Cre⁻ and Cre⁺ mice at 107 dpi with antibodies against ADAM-10-cleaved PrP (sPrP^G228) or total PrP^Sc (POM1; n = 4–5 Hrs^f/fSyn1-Cre mice). Log-rank (Mantel–Cox) test (panels B, C, H) and unpaired, two-tailed Student's t test (panels D, E, I, K, M), **p < 0.01 and ***p < 0.001. Scale bars = 100 µm. Data supported by Extended Data Figures 2-1, 2-2, 2-3, 2-4, and 2-5.