title: Prion-like propagation of human brain-derived alpha-synuclein in transgenic mice expressing human wild-type alpha-synuclein.
abstract: BACKGROUND
  Parkinson's disease (PD) and multiple system atrophy (MSA) are neurodegenerative diseases that are characterized by the intracellular accumulation of alpha-synuclein containing aggregates. Recent increasing evidence suggests that Parkinson's disease and MSA pathology spread throughout the nervous system in a spatiotemporal fashion, possibly by prion-like propagation of alpha-synuclein positive aggregates between synaptically connected areas. Concurrently, intracerebral injection of pathological alpha-synuclein into transgenic mice overexpressing human wild-type alpha-synuclein, or human alpha-synuclein with the familial A53T mutation, or into wild-type mice causes spreading of alpha-synuclein pathology in the CNS. Considering that wild-type mice naturally also express a threonine at codon 53 of alpha-synuclein, it has remained unclear whether human wild-type alpha-synuclein alone, in the absence of endogenously expressed mouse alpha-synuclein, would support a similar propagation of alpha-synuclein pathology in vivo.
  
  
  RESULTS
  Here we show that brain extracts from two patients with MSA and two patients with probable incidental Lewy body disease (iLBD) but not phosphate-buffered saline induce prion-like spreading of pathological alpha-synuclein after intrastriatal injection into mice expressing human wild-type alpha-synuclein. Mice were sacrificed at 3, 6, and 9 months post injection and analyzed neuropathologically and biochemically. Mice injected with brain extracts from patients with MSA or probable iLBD both accumulated intraneuronal inclusion bodies, which stained positive for phosphorylated alpha-synuclein and appeared predominantly within the injected brain hemisphere after 6 months. After 9 months these intraneuronal inclusion bodies had spread to the contralateral hemisphere and more rostral and caudal areas. Biochemical analysis showed that brains of mice injected with brain extracts from patients with MSA and probable iLBD contained hyperphosphorylated alpha-synuclein that also seeded aggregation of recombinant human wild-type alpha-synuclein in a Thioflavin T binding assay.
  
  
  CONCLUSIONS
  Our results indicate that human wild-type alpha-synuclein supports the prion-like spreading of alpha-synuclein pathology in the absence of endogenously expressed mouse alpha-synuclein in vivo.
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Straße 25, Gebäude 13, BMZ1, 53127, Bonn, Germany.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Bernis
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Straße 25, Gebäude 13, BMZ1, 53127, Bonn, Germany.
authors.forename: Julius T
authors.initials: JT
authors.lastname: Babila
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Straße 25, Gebäude 13, BMZ1, 53127, Bonn, Germany.
authors.forename: Sara
authors.initials: S
authors.lastname: Breid
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Straße 25, Gebäude 13, BMZ1, 53127, Bonn, Germany.
authors.forename: Katharina Annick
authors.initials: KA
authors.lastname: Wüsten
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Straße 25, Gebäude 13, BMZ1, 53127, Bonn, Germany.|Department of Neurology, University of Bonn, Sigmund-Freud-Straße 25, 53105, Bonn, Germany.
authors.forename: Ullrich
authors.initials: U
authors.lastname: Wüllner
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Straße 25, Gebäude 13, BMZ1, 53127, Bonn, Germany. erdem@dzne.de.
authors.forename: Gültekin
authors.initials: G
authors.lastname: Tamgüney
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D020961:Lewy Body Disease / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019578:Multiple System Atrophy / Q000473:pathology*; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation; D000071456:Sequestosome-1 Protein; D025801:Ubiquitin / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006360:Heat-Shock Proteins; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D025801:Ubiquitin; D051844:alpha-Synuclein