Astrocytes protect human dopaminergic neurons from α-synuclein accumulation and propagation

Taiji Tsunemi*, Yuta Ishiguro, Asako Yoroisaka, Clarissa Valdez, Kengo Miyamoto, Keiichi Ishikawa, Shinji Saiki, Wado Akamatsu, Nobutaka Hattori, Dimitri Krainc

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

The pathologic hallmark of Parkinson's disease is the accumulation of a-synuclein-containing Lewy bodies/neurites almost exclusively in neurons, and rarely in glial cells. However, emerging evidence suggests that glia such as astrocytes play an important role in the development of α-synuclein pathology. Using induced pluripotent stem-derived dopaminergic neurons and astrocytes from healthy subjects and patients carrying mutations in lysosomal ATP13A2, a monogenic form of synucleinopathy, we found that astrocytes rapidly internalized α-synuclein, and exhibited higher lysosomal degradation rates compared with neurons. Moreover, coculturing astrocytes and neurons led to decreased accumulation of α-synuclein in neurons and consequently diminished interneuronal transfer of α-synuclein. These protective functions of astrocytes were attenuated by ATP13A2 deficiency, suggesting that the loss of ATP13A2 function in astrocytes at least partially contributes to neuronal a-synuclein pathology. Together, our results highlight the importance of lysosomal function in astrocytes in the pathogenesis of synucleinopathies.

Original languageEnglish (US)
Pages (from-to)8618-8628
Number of pages11
JournalJournal of Neuroscience
Volume40
Issue number45
DOIs
StatePublished - Nov 4 2020

Keywords

  • Astrocyte
  • Kufor-Rakeb syndrome
  • Parkinson's disease
  • α-synuclein

ASJC Scopus subject areas

  • Neuroscience(all)

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