Alpha-synuclein aggregation involves a bafilomycin A 1-sensitive autophagy pathway.
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 A 1 (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.
Department of Molecular Neurology, University Hospital, Erlangen, Germany. jochen.klucken@uk-erlangen.de
Jochen
J
Klucken
Anne-Maria
AM
Poehler
Darius
D
Ebrahimi-Fakhari
Jacqueline
J
Schneider
Silke
S
Nuber
Edward
E
Rockenstein
Ursula
U
Schlötzer-Schrehardt
Bradley T
BT
Hyman
Pamela J
PJ
McLean
Eliezer
E
Masliah
Juergen
J
Winkler
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D015415:Biomarkers / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003704:Dementia / Q000378:metabolism / Q000473:pathology; D003902:Detergents / Q000494:pharmacology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D016631:Lewy Bodies / Q000378:metabolism / Q000648:ultrastructure; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008954:Models, Biological; D020836:Protein Structure, Quaternary; D015398:Signal Transduction / Q000187:drug effects*; D012995:Solubility / Q000187:drug effects; D014162:Transfection; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure
D015415:Biomarkers; D003902:Detergents; C477012:MAP1LC3A protein, human; D018942:Macrolides; D008869:Microtubule-Associated Proteins; D051844:alpha-Synuclein; C057620:bafilomycin A