Autophagy modulates SNCA/α-synuclein release, thereby generating a hostile microenvironment

Anne Maria Poehler, Wei Xiang, Philipp Spitzer, Verena Elisabeth Luise May, Holger Meixner, Edward Rockenstein, Oldriska Chutna, Tiago Fleming Outeiro, Juergen Winkler, Eliezer Masliah, Jochen Klucken*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

168 Citations (Scopus)

Abstract

SNCA/α-synuclein aggregation plays a crucial role in synucleinopathies such as Parkinson disease and dementia with Lewy bodies. Aggregating and nonaggregating SNCA species are degraded by the autophagy-lysosomal pathway (ALP). Previously, we have shown that the ALP is not only responsible for SNCA degradation but is also involved in the intracellular aggregation process of SNCA. An additional role of extracellular SNCA in the pathology of synucleinopathies substantiating a prion-like propagation hypothesis has been suggested since released SNCA species and spreading of SNCA pathology throughout neural cells have been observed. However, the molecular interplay between intracellular pathways, SNCA aggregation, release, and response of the local microenvironment remains unknown. Here, we attributed SNCA-induced toxicity mainly to secreted species in a cell culture model of SNCA aggregation and in SNCA transgenic mice: We showed that ALP inhibition by bafilomycinA1 reduced intracellular SNCA aggregation but increased secretion of smaller oligomers that exacerbated microenvironmental response including uptake, inflammation, and cellular damage. Low-aggregated SNCA was predominantly released by exosomes and RAB11A-associated pathways whereas high-aggregated SNCA was secreted by membrane shedding. In summary, our study revealed a novel role of the ALP by linking protein degradation to nonclassical secretion for toxic SNCA species. Thus, impaired ALP in the diseased brain not only limits intracellular degradation of misfolded proteins, but also leads to a detrimental microenvironmental response due to enhanced SNCA secretion. These findings suggest that the major toxic role of SNCA is related to its extracellular species and further supports a protective role of intracellular SNCA aggregation.

Original languageEnglish
Pages (from-to)2171-2192
Number of pages22
JournalAutophagy
Volume10
Issue number12
DOIs
Publication statusPublished - 1 Dec 2014
Externally publishedYes

Keywords

  • Inflammation
  • Lysosomal degradation
  • Parkinson disease
  • Protein aggregation
  • Secretion
  • Synucleinopathies
  • α-synuclein

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