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. 2010 Sep 8;30(36):12094-102.
doi: 10.1523/JNEUROSCI.2417-10.2010.

Prion strain interactions are highly selective

K Peter R Nilsson  1 , Shivanjali Joshi-Barr, Olivia Winson, Christina J Sigurdson
Affiliations

Prion strain interactions are highly selective

K Peter R Nilsson et al. J Neurosci. .

Abstract

Various misfolded and aggregated neuronal proteins commonly coexist in neurodegenerative disease, but whether the proteins coaggregate and alter the disease pathogenesis is unclear. Here, we used mixtures of distinct prion strains, which are believed to differ in conformation, to test the hypothesis that two different aggregates interact and change the disease in vivo. We tracked two prion strains in mice histopathologically and biochemically, as well as by spectral analysis of plaque-bound PTAA (polythiophene acetic acid), a conformation-sensitive fluorescent amyloid ligand. We found that prion strains interacted in a highly selective and strain-specific manner, with (1) no interaction, (2) hybrid plaque formation, or (3) blockage of one strain by a second (interference). The hybrid plaques were maintained on additional passage in vivo and each strain seemed to maintain its original conformational properties, suggesting that one strain served only as a scaffold for aggregation of the second strain. These findings not only further our understanding of prion strain interactions but also directly demonstrate interactions that may occur in other protein aggregate mixtures.

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Figures

Figure 1.
Figure 1.
Survival period (left) and brain histopathology (right) of mice inoculated with individual prion strains or a mixture of two strains. For the histopathology, a lesion severity score (spongiform change, astrogliosis, and PrPSc deposition) was plotted for 10 brain regions (see Materials and Methods). Each ring represents one point. The two individual strains and the mixture are represented by the same color as in the survival plot.
Figure 2.
Figure 2.
Hippocampal PrPSc deposition is markedly reduced in the mNS/mBSE strain mixture. Hematoxylin and eosin (HE) (top) and PrP immunohistochemistry (bottom) from mNS and mNS/mBSE mixtures. The inset in the HE shows a higher magnification of the spongiform change in the same region. A–D, Hippocampus (A) and hypothalamus (B) of mice infected with mNS shows the spongiform encephalopathy and PrPSc deposition (arrows) in two representative mice, whereas C and D show the same regions from mice infected with the mNS/mBSE mixture. The hippocampus (C), but not the hypothalamus (D), has minimal spongiform change and a lack of PrPSc staining in the mice infected with the mNS/mBSE mixture. Scale bars: A, B, 500 μm; inset, 100 μm.
Figure 3.
Figure 3.
Plaque morphology and Congo red staining properties of the individual prion strains and the mixtures in the brain. A, Individual strains. Dense mCWD plaques are characterized by a dark peripheral border, whereas mNS plaques are lighter staining with an irregular border and mBSE plaques appear oval and homogenous. All mCWD plaques and only a small subpopulation of mNS and mBSE plaques stain with Congo red. B, Mixed strains show plaques of varying morphology reminiscent of the individual strains. The mNS/mBSE plaque population appeared as small plaques with irregular contours. Scale bars: A, B (PrP), 100 μm; B (Congo red), 50 μm.
Figure 4.
Figure 4.
Brain from mice infected with mNS, mBSE, or an mNS/mBSE mixture were proteinase K-treated and immunoblotted using either C-terminal (POM1) or N-terminal (POM2) anti-PrP antibodies. The PK-treated mBSE core fragment is smaller than the mNS (see top blot) and is not recognized by the POM2 antibody (epitope on the octarepeats: amino acids 58–64, 66–72, 74–80, 82–88). There was an incomplete PK digest of the sample in lane 7.
Figure 5.
Figure 5.
PTAA staining of PrP deposits in single and mixed prion strains in brain cryosections. A, Spectra of PTAA bound to mCWD and mNS plaques (left panel). Correlation diagram of the ratio of light intensity emitted at 532/emission maximum (R532/Emax) and 532/641 (R532/641) from PTAA bound to mCWD, mNS, or mNS/mCWD plaques in individual mice (right panel). B, C, Fluorescence images of PTAA bound to plaques in NS/mCWD-infected mice: a typical mNS plaque (B), and mCWD (yellow) and mNS (yellow-red) plaques (top panel) and hybrid plaques (bottom panel) in the corpus callosum region (C). Middle and right panels, Pseudocolor visualizations of the two distinct types of amyloid deposits after spectral unmixing show pixels that have the same spectrum: PTAA signals are represented in green (mCWD; green spectrum) or red (mNS; red spectrum). The hybrid plaques have a mCWD core in green (green arrow) and a mNS border in yellow-red (red arrow) (bottom left). D, E, Spectra (left panel) and correlation diagrams (right panel) of PTAA bound to mCWD and mBSE plaques (D), and mNS and mBSE plaques (E). F, G, Pseudocolor visualization of PTAA bound to mBSE (red) or mCWD (green) plaques in the mCWD/mBSE mice after spectral unmixing (F) and mBSE (red) or mNS (red) plaques in the mNS/mBSE mice (G). mBSE and mNS show similar spectral profiles. Scale bars: B, C (bottom), F, 20 μm; C (top), 50 μm.
Figure 6.
Figure 6.
Survival period, brain histopathology, and PTAA spectral profile of mice inoculated with a mixture of mNS and mCWD. A, Comparison of the survival period for first and second passage of mNS/mCWD (left panel) or for the 50:50 or 10:90 mixtures of mNS/mCWD (right panel). mNS and mCWD are shown for comparison (left panel). B, Lesion severity score (spongiform change, astrogliosis, and PrPSc deposition) plotted for 10 brain regions (see Materials and Methods). Each ring represents one point. The two individual strains and the mixture are represented by the same color as in the survival plot. C, F, Correlation diagrams of the ratio of light intensity emitted at 532/emission maximum (R532/Emax) and 532/641 (R532/641) from PTAA bound to mCWD/mNS plaques in individual mice from the first and second passage (C), and from the 50:50 or 10:90 mNS:mCWD mixture (F). D, G, Fluorescence image of a typical mNS plaque stained by PTAA. E, H, Fluorescence images of PTAA bound to mCWD and mNS plaques in mice inoculated with the second-passage mNS/mCWD (E) and with the 10:90 mixture (H) (left panels). E, H, Pseudocolor visualizations show the two distinct spectra from amyloid deposits after spectral unmixing: PTAA emission spectra are represented in green (mCWD) (middle panel) or red (mNS) (right panel). Scale bars: D, G, 20 μm; E, H, 25 μm.
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