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Acta Neuropathologica
Published in: Acta Neuropathologica 3/2019

01-03-2019 | Original Paper

Multiple system atrophy prions retain strain specificity after serial propagation in two different Tg(SNCA*A53T) mouse lines

Authors: Amanda L. Woerman, Abby Oehler, Sabeen A. Kazmi, Jisoo Lee, Glenda M. Halliday, Lefkos T. Middleton, Steve M. Gentleman, Daniel A. Mordes, Salvatore Spina, Lea T. Grinberg, Steven H. Olson, Stanley B. Prusiner

Published in: Acta Neuropathologica | Issue 3/2019

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Abstract

Previously, we reported that intracranial inoculation of brain homogenate from multiple system atrophy (MSA) patient samples produces neurological disease in the transgenic (Tg) mouse model TgM83+/−, which uses the prion protein promoter to express human α-synuclein harboring the A53T mutation found in familial Parkinson’s disease (PD). In our studies, we inoculated MSA and control patient samples into Tg mice constructed using a P1 artificial chromosome to express wild-type (WT), A30P, and A53T human α-synuclein on a mouse α-synuclein knockout background [Tg(SNCA+/+)Nbm, Tg(SNCA*A30P+/+)Nbm, and Tg(SNCA*A53T+/+)Nbm]. In contrast to studies using TgM83+/− mice, motor deficits were not observed by 330–400 days in any of the Tg(SNCA)Nbm mice after inoculation with MSA brain homogenates. However, using a cell-based bioassay to measure α-synuclein prions, we found brain homogenates from Tg(SNCA*A53T+/+)Nbm mice inoculated with MSA patient samples contained α-synuclein prions, whereas control mice did not. Moreover, these α-synuclein aggregates retained the biological and biochemical characteristics of the α-synuclein prions in MSA patient samples. Intriguingly, Tg(SNCA*A53T+/+)Nbm mice developed α-synuclein pathology in neurons and astrocytes throughout the limbic system. This finding is in contrast to MSA-inoculated TgM83+/− mice, which develop exclusively neuronal α-synuclein aggregates in the hindbrain that cause motor deficits with advanced disease. In a crossover experiment, we inoculated TgM83+/− mice with brain homogenate from two MSA patient samples or one control sample first inoculated, or passaged, in Tg(SNCA*A53T+/+)Nbm animals. Additionally, we performed the reverse experiment by inoculating Tg(SNCA*A53T+/+)Nbm mice with brain homogenate from the same two MSA samples and one control sample first passaged in TgM83+/− animals. The TgM83+/− mice inoculated with mouse-passaged MSA developed motor dysfunction and α-synuclein prions, whereas the mouse-passaged control sample had no effect. Similarly, the mouse-passaged MSA samples induced α-synuclein prion formation in Tg(SNCA*A53T+/+)Nbm mice, but the mouse-passaged control sample did not. The confirmed transmission of α-synuclein prions to a second synucleinopathy model and the ability to propagate prions between two distinct mouse lines while retaining strain-specific properties provides compelling evidence that MSA is a prion disease.
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Metadata
Title
Multiple system atrophy prions retain strain specificity after serial propagation in two different Tg(SNCA*A53T) mouse lines
Authors
Amanda L. Woerman
Abby Oehler
Sabeen A. Kazmi
Jisoo Lee
Glenda M. Halliday
Lefkos T. Middleton
Steve M. Gentleman
Daniel A. Mordes
Salvatore Spina
Lea T. Grinberg
Steven H. Olson
Stanley B. Prusiner
Publication date
01-03-2019
Publisher
Springer Berlin Heidelberg
Published in
Acta Neuropathologica / Issue 3/2019
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI
https://doi.org/10.1007/s00401-019-01959-4

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