Transmission of soluble and insoluble α-synuclein to mice

Daryl Rhys Jones, Marion Delenclos, Ann Marie T. Baine, Michael De Ture, Melissa E. Murray, Dennis W. Dickson, Pamela J. McLean

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

The neurodegenerative synucleinopathies, which include Parkinson disease, multiple-system atrophy, and Lewy body disease, are characterized by the presence of abundant neuronal inclusions called Lewy bodies and Lewy neurites. These disorders remain incurable, and a greater understanding of the pathologic processes is needed for effective treatment strategies to be developed. Recent data suggest that pathogenic misfolding of the presynaptic protein, α-synuclein (α-syn), and subsequent aggregation and accumulation are fundamental to the disease process. It is hypothesized that the misfolded isoform is able to induce misfolding of normal endogenous α-syn, much like what occurs in the prion diseases. Recent work highlighting the seeding effect of pathogenic α-syn has largely focused on the detergent-insoluble species of the protein. In this study, we performed intracerebral inoculations of the sarkosyl-insoluble or sarkosyl-soluble fractions of human Lewy body disease brain homogenate and show that both fractions induce CNS pathology in mice at 4 months after injection. Disease-associated deposits accumulated both near and distal to the site of the injection, suggesting a cell-to-cell spread via recruitment of α-syn. These results provide further insight into the prion-like mechanisms of α-syn and suggest that disease-associated α-syn is not homogeneous within a single patient but might exist in both soluble and insoluble isoforms.

Original languageEnglish (US)
Pages (from-to)1158-1169
Number of pages12
JournalJournal of Neuropathology and Experimental Neurology
Volume74
Issue number12
DOIs
StatePublished - 2015

Keywords

  • Lewy body disease
  • Parkinson disease
  • Prion
  • Prion-like
  • Soluble prion
  • α-Synuclein

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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