Replication of multiple system atrophy prions in primary astrocyte cultures from transgenic mice expressing human α-synuclein

Acta Neuropathol Commun. 2019 May 20;7(1):81. doi: 10.1186/s40478-019-0703-9.

Abstract

Glial cytoplasmic inclusions (GCIs) containing aggregated and hyperphosphorylated α-synuclein are the signature neuropathological hallmark of multiple system atrophy (MSA). Native α-synuclein can adopt a prion conformation that self-propagates and spreads throughout the brain ultimately resulting in neurodegeneration. A growing body of evidence argues that, in addition to oligodendrocytes, astrocytes contain α-synuclein inclusions in MSA and other α-synucleinopathies at advanced stages of disease. To study the role of astrocytes in MSA, we added MSA brain homogenate to primary cultures of astrocytes from transgenic (Tg) mouse lines expressing human α-synuclein. Astrocytes from four Tg lines, expressing either wild-type or mutant (A53T or A30P) human α-synuclein, propagated and accumulated α-synuclein prions. Furthermore, we found that MSA-infected astrocytes formed two morphologically distinct α-synuclein inclusions: filamentous and granular. Both types of cytoplasmic inclusions shared several features characteristic of α-synuclein inclusions in synucleinopathies: hyperphosphorylation preceded by aggregation, ubiquitination, thioflavin S-positivity, and co-localization with p62. Our findings demonstrate that human α-synuclein forms distinct inclusion morphologies and propagates within cultured Tg astrocytes exposed to MSA prions, indicating that α-synuclein expression determines the tropism of inclusion formation in certain cells. Thus, our work may prove useful in elucidating the role of astrocytes in the pathogenic mechanisms that feature in neurodegeneration caused by MSA prions.

Keywords: Astrocytes; MSA; Prion; Proteinopathies; α-Synuclein.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / metabolism
  • Astrocytes / pathology*
  • Cells, Cultured
  • Dendritic Spines / metabolism
  • Dendritic Spines / pathology
  • Humans
  • Inclusion Bodies / metabolism
  • Inclusion Bodies / pathology
  • Mice, Transgenic
  • Multiple System Atrophy / metabolism
  • Multiple System Atrophy / pathology*
  • Prions / metabolism*
  • Recombinant Proteins / administration & dosage
  • alpha-Synuclein / administration & dosage
  • alpha-Synuclein / metabolism*

Substances

  • Prions
  • Recombinant Proteins
  • alpha-Synuclein