Multiple system atrophy prions replicate in Tg(SNCAA53T) mice and induce glial pathology throughout the limbic system

O12 Multiple system atrophy prions replicate in Tg(SNCAA53T) mice and induce glial pathology throughout the limbic system 

Amanda L. Woerman (1,2), Krista McFarland (1,2), Sabeen Kazmi (1), Abby Oehler (1), Kurt Giles (1,2), Daniel A. Mordes (3), Lefkos T. Middleton (4), Steve M. Gentleman (5), Steven H. Olson (1,2), and Stanley B. Prusiner (1,2,6) 

(1) Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California, San Francisco, CA, United States (2) Department of Neurology, University of California, San Francisco, CA, United States (3) C.S. Kubik Laboratory for Neuropathology, Department of Pathology, Massachusetts General Hospital, Boston, MA, United States (4) Ageing Research Unit, School of Public Health, Imperial College London, London, United Kingdom (5) Centre for Neuroinflammation and Neurodegeneration, Department of Medicine, Imperial College London, London, United Kingdom (6) Department of Biochemistry and Biophysics, University of California, San Francisco, CA, United States. 

In a series of recent publications, multiple system atrophy (MSA) was identified as a prion disease following the transmission of neurological symptoms to transgenic mice expressing A53T mutant human α-synuclein (TgM83+/-). Here we inoculated mice expressing wild-type (WT), A30P, and A53T human α-synuclein on a mouse knockout background [Tg(SNCA), Tg(SNCAA30P), and Tg(SNCAA53T), respectively]. Unlike studies using TgM83+/- mice, motor deficits were not observed in animals expressing WT or mutant α-synuclein 400 and 330 days post inoculation, respectively. However, brain homogenates from the Tg(SNCAA53T) mice contained α-synuclein prions, as measured in the αsyn140*A53T–YFP cell assay, and showed a similar biological activity profile to MSA prions in a panel of α-synuclein–YFP cell lines. Moreover, these mice developed hyperphosphorylated αsynuclein neuropathology throughout the limbic system, particularly in the hippocampus and entorhinal cortex, which co-localized with antibodies for glial cells following immunostaining. Importantly, this pathology is distinct from the induced pathology in the TgM83+/- mice, which develop neuronal α-synuclein aggregates throughout the hindbrain causing motor deficits with advanced disease. In contrast, the Tg(SNCAA53T) mice have no α-synuclein accumulation in the cerebellum or brainstem. Brain homogenates from Tg(SNCAA53T) mice inoculated with two MSA cases or one control sample were then used to inoculate TgM83+/- animals. Serial passaging of MSA induced motor dysfunction and α-synuclein prion formation in the TgM83+/- mice, but the control sample had no effect on the animals. The confirmed transmission of α-synuclein prions to a second synucleinopathy model and the ability to propagate the prions between two distinct mouse lines with retention of strain properties provides definitive evidence that MSA is a prion disease. ...

Prion 2018 Conference Abstract https://prion2018.org/

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