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Authors: 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 and Juergen Winkler

Jochen Klucken

Corresponding author: jochen.klucken@uk-erlangen.de
Department of Molecular Neurology; University Hospital; Erlangen, Germany

Anne-Maria Poehler

Department of Molecular Neurology; University Hospital; Erlangen, Germany

Darius Ebrahimi-Fakhari

MassGeneral Institute for Neurodegenerative Disease; Department of Neurology; Massachusetts General Hospital and Harvard Medical School; Charlestown, MA USA

Jacqueline Schneider

Department of Molecular Neurology; University Hospital; Erlangen, Germany

Silke Nuber

Department of Neurosciences; University of California San Diego; La Jolla, CA USA; Department of Medical Genetics; University Hospital; Tuebingen, Germany

Edward Rockenstein

Department of Neurosciences; University of California San Diego; La Jolla, CA USA

Ursula Schlötzer-Schrehardt

Department of Ophthalmology; University Hospital; Erlangen, Germany

Bradley T. Hyman

MassGeneral Institute for Neurodegenerative Disease; Department of Neurology; Massachusetts General Hospital and Harvard Medical School; Charlestown, MA USA

Pamela J. McLean

MassGeneral Institute for Neurodegenerative Disease; Department of Neurology; Massachusetts General Hospital and Harvard Medical School; Charlestown, MA USA

Eliezer Masliah

Department of Neurosciences; University of California San Diego; La Jolla, CA USA

Juergen Winkler

Department of Molecular Neurology; University Hospital; Erlangen, Germany; Department of Neurosciences; University of California San Diego; La Jolla, CA USA

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 α-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.

Received: August 3, 2011; Accepted: January 14, 2012; Published Online: May 1, 2012

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