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Transmissible α-synuclein seeding activity in brain and stomach of patients with Parkinson's disease.

Authors
  • Thomzig, Achim1
  • Wagenführ, Katja1, 2
  • Pinder, Phillip1
  • Joncic, Marion1
  • Schulz-Schaeffer, Walter J3
  • Beekes, Michael4
  • 1 Prion and Prionoid Research Unit, ZBS 6-Proteomics and Spectroscopy, ZBS-Centre for Biological Threats and Special Pathogens, Robert Koch Institute, Nordufer 20, 13353, Berlin, Germany. , (Germany)
  • 2 State Office for Health and Social Affairs (LAGeSo), Berlin, Germany. , (Germany)
  • 3 Institute of Neuropathology, Faculty of Medicine, Saarland University, Homburg, Germany. , (Germany)
  • 4 Prion and Prionoid Research Unit, ZBS 6-Proteomics and Spectroscopy, ZBS-Centre for Biological Threats and Special Pathogens, Robert Koch Institute, Nordufer 20, 13353, Berlin, Germany. [email protected] , (Germany)
Type
Published Article
Journal
Acta Neuropathologica
Publisher
Springer-Verlag
Publication Date
Jun 01, 2021
Volume
141
Issue
6
Pages
861–879
Identifiers
DOI: 10.1007/s00401-021-02312-4
PMID: 33895878
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Cerebral deposition of abnormally aggregated α-synuclein (αSyn) is a neuropathological hallmark of Parkinson's disease (PD). PD-associated αSyn (αSynPD) aggregates can act as proteinaceous nuclei ("seeds") able of self-templated propagation. Since this is strikingly reminiscent to properties of proteinaceous infectious particles (prions), lessons learned from prion diseases suggest to test whether transferred αSynPD can propagate and induce neurological impairments or disease in a new host. Two studies that addressed this question provided divergent results. Intracerebral (i.c.) injection of Lewy body extracts from PD patients caused cerebral αSyn pathology, as well as nigrostriatal neurodegeneration, of wild-type mice and macaques, with the mice also showing motor impairments (Recasens et al. 2014, Ann Neurol 75:351-362). In contrast, i.c. transmission of homogenates from PD brains did not stimulate, after "> 360" days post-injection (dpi), pathological αSyn conversion or clinical symptoms in transgenic TgM83+/- mice hemizygously expressing mutated (A53T) human αSyn (Prusiner et al. 2015, PNAS 112:E5308-E5317). To advance the assessment of possible αSynPD hazards by providing further data, we examined neuropathological and clinical effects upon i.c. transmission of brain, stomach wall and muscle tissue as well as blood from PD patients in TgM83+/- mice up to 612 dpi. This revealed a subtle, yet distinctive stimulation of localized αSyn aggregation in the somatodendritic compartment and dystrophic neurites of individual or focally clustered cerebral neurons after challenge with brain and stomach wall homogenates. No such effect was observed with transmitted blood or homogenized muscle tissue. The detected stimulation of αSyn aggregation was not accompanied by apparent motor impairments or overt neurological disease in TgM83+/- mice. Our study substantiated that transmitted αSynPD seeds, including those from the stomach wall, are able to propagate in new mammalian hosts. The consequences of such propagation and potential safeguards need to be further investigated.

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