Abstract
BackgroundThe accumulation and aggregation of α-synuclein in nerve cells and glia are characteristic features of a number of neurodegenerative diseases termed synucleinopathies. α-Synuclein is a highly soluble protein which in a nucleation dependent process is capable of self-aggregation. The causes underlying aggregate formation are not yet understood, impairment of the proteolytic degradation systems might be involved.Methodology/Principal FindingsIn the present study the possible aggregate clearing effects of the geldanamycin analogue 17-AAG (17-(Allylamino)-17-demethoxygeldanamycin) was investigated. Towards this, an oligodendroglial cell line (OLN-93 cells), stably expressing human α-synuclein (A53T mutation) was used. In these cells small punctate aggregates, not staining with thioflavine S, representing prefibrillary aggregates, occur characteristically. Our data demonstrate that 17-AAG attenuated the formation of α-synuclein aggregates by stimulating macroautophagy. By blocking the lysosomal compartment with NH4Cl the aggregate clearing effects of 17-AAG were abolished and α-synuclein deposits were enlarged. Analysis of LC3-II immunoreactivity, which is an indicator of autophagosome formation, further revealed that 17-AAG led to the recruitment of LC3-II and to the formation of LC3 positive puncta. This effect was also observed in cultured oligodendrocytes derived from the brains of newborn rats. Inhibition of macroautophagy by 3-methyladenine prevented 17-AAG induced occurrence of LC3 positive puncta as well as the removal of α-synuclein aggregates in OLN-A53T cells.ConclusionsOur data demonstrate for the first time that 17-AAG not only causes the upregulation of heat shock proteins, but also is an effective inducer of the autophagic pathway by which α-synuclein can be removed. Hence geldanamycin derivatives may provide a means to modulate autophagy in neural cells, thereby ameliorating pathogenic aggregate formation and protecting the cells during disease and aging.
Highlights
Our data demonstrate for the first time that 17-AAG causes the upregulation of heat shock proteins, and is an effective inducer of the autophagic pathway by which a-synuclein can be removed
In Parkinson’s disease (PD) the accumulation and aggregation of a-synuclein in neurons is a characteristic feature, while a-synuclein positive glial cytoplasmic inclusions (GCIs) originating in oligodendrocytes are the histological hallmark of multiple system atrophy (MSA), a specific adult onset neurodegenerative disease with symptoms of Parkinsonism [1,2]
In the present study we have investigated the possible aggregateclearing effects of the geldanamycin analogue 17-AAG. 17-AAG is currently in clinical trials as an anticancer drug, binds to and inhibits HSP90 [25] and triggers the activation of a heat shock response in mammalian cells [26,27]
Summary
In Parkinson’s disease (PD) the accumulation and aggregation of a-synuclein in neurons is a characteristic feature, while a-synuclein positive glial cytoplasmic inclusions (GCIs) originating in oligodendrocytes are the histological hallmark of multiple system atrophy (MSA), a specific adult onset neurodegenerative disease with symptoms of Parkinsonism [1,2]. These inclusions are further characterized by staining with antibodies against ubiquitin and a variety of heat shock proteins (HSPs), the small HSP aB-crystallin. The causes underlying aggregate formation are not yet understood, impairment of the proteolytic degradation systems might be involved
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