Alpha-synuclein aggregation involves a bafilomycin A1-sensitive autophagy pathway

Jochen Klucken, Anne Maria Poehler, Darius Ebrahimi-Fakhari, Jacqueline Schneider, Silke Nuber, Edward Rockenstein, Ursula Schlötzer-Schrehardt, Bradley T. Hyman, Pamela J. McLean, Eliezer Masliah, Juergen Winkler

Research output: Contribution to journalArticlepeer-review

80 Scopus citations

Abstract

Synucleinopathies like Parkinson disease and dementia with Lewy bodies (DLB) are characterized by α-synuclein aggregates within neurons (Lewy bodies) and their processes (Lewy neurites). Whereas α-synuclein has been genetically linked to the disease process, the pathological relevance of α-synuclein aggregates is still debated. Impaired degradation is considered to result in aggregation of α-synuclein. In addition to the ubiquitin-proteasome degradation, the autophagy-lysosomal pathway (ALP) is involved in intracellular degradation processes for a-synuclein. Here, we asked if modulation of ALP affects α-synuclein aggregation and toxicity. We have identified an induction of the ALP markers LAMP-2A and LC3-II in human brain tissue from DLB patients, in a transgenic mouse model of synucleinopathy, and in a cell culture model for α-synuclein aggregation. ALP inhibition using bafilomycin A1 (BafA1) significantly potentiates toxicity of aggregated α-synuclein species in transgenic mice and in cell culture. Surprisingly, increased toxicity is paralleled by reduced aggregation in both in vivo and in vitro models. The dichotomy of effects on aggregating and nonaggregating species of α-synuclein was specifically sensitive to BafA1 and could not be reproduced by other ALP inhibitors. The present study expands on the accumulating evidence regarding the function of ALP for α-synuclein degradation by isolating an aggregation specific, BafA1-sensitive, ALP-related pathway. Our data also suggest that protein aggregation may represent a detoxifying event rather than being causal for cellular toxicity.

Original languageEnglish (US)
Pages (from-to)754-766
Number of pages13
JournalAutophagy
Volume8
Issue number5
DOIs
StatePublished - May 2012

Keywords

  • Alpha-synuclein
  • Dementia with lewy bodies (DLB)
  • Lewy body
  • Lysosomal degradation
  • Parkinson disease (PD)
  • Protein aggregation

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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