Posttranslational modifications define course of prion strain adaptation and disease phenotype
Natallia Makarava, … , Kara Molesworth, Ilia V. Baskakov
Natallia Makarava, … , Kara Molesworth, Ilia V. Baskakov
Published June 2, 2020
Citation Information: J Clin Invest. 2020;130(8):4382-4395. https://doi.org/10.1172/JCI138677.
View: Text | PDF
Research Article Infectious disease Neuroscience

Posttranslational modifications define course of prion strain adaptation and disease phenotype

Abstract

Posttranslational modifications are a common feature of proteins associated with neurodegenerative diseases including prion protein (PrPC), tau, and α-synuclein. Alternative self-propagating protein states or strains give rise to different disease phenotypes and display strain-specific subsets of posttranslational modifications. The relationships between strain-specific structure, posttranslational modifications, and disease phenotype are poorly understood. We previously reported that among hundreds of PrPC sialoglycoforms expressed by a cell, individual prion strains recruited PrPC molecules selectively, according to the sialylation status of their N-linked glycans. Here we report that transmission of a prion strain to a new host is accompanied by a dramatic shift in the selectivity of recruitment of PrPC sialoglycoforms, giving rise to a self-propagating scrapie isoform (PrPSc) with a unique sialoglycoform signature and disease phenotype. The newly emerged strain has the shortest incubation time to disease and is characterized by colocalization of PrPSc with microglia and a very profound proinflammatory response, features that are linked to a unique sialoglycoform composition of PrPSc. The current work provides experimental support for the hypothesis that strain-specific patterns of PrPSc sialoglycoforms formed as a result of selective recruitment dictate strain-specific disease phenotypes. This work suggests a causative relationship between a strain-specific structure, posttranslational modifications, and disease phenotype.

Authors

Natallia Makarava, Jennifer Chen-Yu Chang, Kara Molesworth, Ilia V. Baskakov

×

Figure 1

Adaptation of SSLOW to mice.

Options: View larger image (or click on image) Download as PowerPoint
Adaptation of SSLOW to mice. (A) Adaptation of hamster SSLOW to mouse Pr...
(A) Adaptation of hamster SSLOW to mouse PrPC in sPMCAb seeded with 103-fold-diluted SSLOW BHs and conducted using mouse normal BHs. Corresponding nonseeded sPMCAb and serial dilutions of SSLOW BHs in the absence of amplification are shown as references. (B) Left: Western blot analysis of PrPSc in mice inoculated with the hamster-derived SSLOW, mouse sPMCAb-adapted SSLOW, or noninoculated aged-matched controls. Products of the tenth sPMCAb round were used for inoculation. Right: Comparison of the PrPSc amounts in passages 1 and 2 of sPMCAb-adapted SSLOW. Animal number 3 was used for serial transmission. In A and B, all samples, with the exception of lane 1 (–PK), were treated with PK. (C) Western blot analysis of PrPSc from passages 2–6. (D) Change in the percentage of di-, mono-, and unglycosylated PrPSc as a function of serial passage. Data presented as individual animals and mean ± SD (n = 3 for passage 2 and n = 6 for the other groups). (E) Box-and-whisker plot of incubation time to clinical disease in i.c.-inoculated animals as a function of serial passage. The midline of the box-and-whisker plot denotes the median, the x represents the mean, and the ends of the box plot denote the 25th and 75th percentiles. For passage 2, only females (F) were used (n = 8); both males (M) and females were used for the remaining passages: n = 8 F + 5 M in passage 3, n = 4 F + 5 M in passage 4, n = 5 F + 5 M in passage 5, and n = 8 F + 5 M in passage 6. Data presented as the mean ± SD. ****P ≤ 0.0001 by 1-way ANOVA with Dunnett’s T3 multiple-comparisons test. (F) Kaplan-Meier survival plot for mice from serial passages 2–6. The survival curve for SSLOW-inoculated hamsters is provided as reference (41, 81). Western blots (A) were stained with antibody SAF-84 and in B and C with antibody ab3531.