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. 2023 Mar 30;145(5):541–559. doi: 10.1007/s00401-023-02562-4

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© The Author(s) 2023

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 4 — MSA fibrils propagate synucleinopathy from the urinary tract in vivo. To assess peripheral ɑSyn propagation and how oligodendroglial cellular environment can impact the spreading of ɑSyn, ɑSyn fibrils were amplified from human MSA brain. a After addition of homogenized and purified MSA brain, ɑSyn monomers were efficiently seeded into fibrillar ɑSyn. b Different passages with 5 rounds of amplification generates distinctive MSA fibrils with a distinct ThT profile compared to fibrils generated with recombinant ɑSyn only. c Two different animal models are used. Both models express human ɑSyn in spinal cord oligodendrocytes but with differences in expression pattern. Transgenic human ɑSyn mice (hu-ɑSyn mice), express soluble human ɑSyn in cell bodies of oligodendrocytes of the spinal cord (open arrows, upper panel) whereas ODC-ɑSyn mice express human ɑSyn in cell bodies and myelin sheets of mature oligodendrocytes in spinal cord anterior columns (lower panel, closed arrows). d Representative images of amplified fibrils of MSA brain recorded by TEM (scale bar 100 nm). e Fibrils from MSA brain were injected in two opposite sides of the detrusor muscle of the urinary bladder adjacent to the urethral opening and close the pelvic plexus. After 9 months of injection, animals showed f urinary voiding and g gait deficits with loss of fine motor control of h right and i left paws for ODC-ɑSyn mice injected with MSA fibrils but not with monomers (n ≥ 6, *p < 0.05, **p < 0.01 with mixed-effects analysis of two-way ANOVA and Tukey post hoc correction for multiple comparison). Motor behavior was measured via automated Catwalk gait analysis. No effects were observed in hu-ɑSyn mice injected with MSA fibrils. j Analysis of PSer129-ɑSyn in spinal cord anterior columns and anterior horns reveals that in ODC-ɑSyn mice injection of MSA strains into the urinary bladder leads to k increased ɑSyn pathology accompanied by l microglial inflammation in the anterior columns (n ≥ 6, s.e.m. *p < 0.05, ***p < 0.001 with mixed-effects analysis of two-way ANOVA and Tukey post hoc correction for multiple comparison)