Multiple system atrophy prions transmit neurological disease to mice expressing wild-type human α-synuclein.

Autor: Holec SAM; Department of Biology and Institute for Applied Life Sciences, University of Massachusetts Amherst, 240 Thatcher Road, Amherst, MA, 01003, USA., Lee J; Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, 94153, USA., Oehler A; Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, 94153, USA., Ooi FK; Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, 94153, USA., Mordes DA; Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, 94153, USA.; Department of Pathology, University of California San Francisco, San Francisco, CA, USA., Olson SH; Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, 94153, USA.; Department of Neurology, University of California San Francisco, San Francisco, CA, USA.; Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, San Diego, CA, USA., Prusiner SB; Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, 94153, USA. stanley.prusiner@ucsf.edu.; Department of Neurology, University of California San Francisco, San Francisco, CA, USA. stanley.prusiner@ucsf.edu.; Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA. stanley.prusiner@ucsf.edu., Woerman AL; Department of Biology and Institute for Applied Life Sciences, University of Massachusetts Amherst, 240 Thatcher Road, Amherst, MA, 01003, USA. awoerman@umass.edu.; Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, 94153, USA. awoerman@umass.edu.; Department of Neurology, University of California San Francisco, San Francisco, CA, USA. awoerman@umass.edu.
Jazyk: angličtina
Zdroj: Acta neuropathologica [Acta Neuropathol] 2022 Oct; Vol. 144 (4), pp. 677-690. Date of Electronic Publication: 2022 Aug 26.
DOI: 10.1007/s00401-022-02476-7
Abstrakt: In multiple system atrophy (MSA), the protein α-synuclein misfolds into a prion conformation that self-templates and causes progressive neurodegeneration. While many point mutations in the α-synuclein gene, SNCA, have been identified as the cause of heritable Parkinson's disease (PD), none have been identified as causing MSA. To examine whether MSA prions can transmit disease to mice expressing wild-type (WT) human α-synuclein, we inoculated transgenic (Tg) mice denoted TgM20 +/- with brain homogenates prepared from six different deceased MSA patients. All six samples transmitted CNS disease to the mice, with an average incubation period of ~ 280 days. Interestingly, TgM20 +/- female mice developed disease > 60 days earlier than their male counterparts. Brains from terminal mice contained phosphorylated α-synuclein throughout the hindbrain, consistent with the distribution of α-synuclein inclusions in MSA patients. In addition, using our α-syn-YFP cell lines, we detected α-synuclein prions in brain homogenates prepared from terminal mice that retained MSA strain properties. To our knowledge, the studies described here are the first to show that MSA prions transmit neurological disease to mice expressing WT SNCA and that the rate of transmission is sex dependent. By comparison, TgM20 +/- mice inoculated with WT preformed fibrils (PFFs) developed severe neurological disease in ~ 210 days and exhibited robust α-synuclein neuropathology in both limbic regions and the hindbrain. Brain homogenates from these animals exhibited biological activities that are distinct from those found in MSA-inoculated mice when tested in the α-syn-YFP cell lines. Differences between brains from MSA-inoculated and WT PFF-inoculated mice potentially argue that α-synuclein prions from MSA patients are distinct from the PFF inocula and that PFFs do not replicate MSA strain biology.
(© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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