17-AAG Induces Cytoplasmic α-Synuclein Aggregate Clearance by Induction of Autophagy
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BACKGROUND: The accumulation and aggregation of alpha-synuclein in nerve cells and glia are characteristic features of a number of neurodegenerative diseases termed synucleinopathies. alpha-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 FINDINGS: In 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 alpha-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 alpha-synuclein aggregates by stimulating macroautophagy. By blocking the lysosomal compartment with NH(4)Cl the aggregate clearing effects of 17-AAG were abolished and alpha-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 alpha-synuclein aggregates in OLN-A53T cells. CONCLUSIONS: Our 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 alpha-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.
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- Authors
- Riedel, M., Goldbaum, O., Schwarz, L., Schmitt, S., & Richter-Landsberg, C.
- Affiliations
- Carl von Ossietzky Universität Oldenburg (DE)
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2010-01-18
- Volume
- 5
- Issue
- 1
- Pages
- e8753
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2807466
- OpenAlex
- W2014749287
- Cited by
- 87
- References
- 59
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 4 · 2022: 4 · 2021: 3 · 2020: 2 · 2019: 5 · 2018: 2 · 2017: 2 · 2016: 6 · 2015: 6 · 2014: 8 · 2013: 12 · 2012: 11
- FWCI
- 7.44
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- 17-AAG, geldanamycin derivatives, alpha-synuclein, protein aggregation, autophagy, macroautophagy, synucleinopathies, A53T mutation, oligodendrocytes, LC3, lysosomal degradation, heat shock proteins, neurodegeneration
- MeSH terms
- Animals, Autophagy, Cell Line, Cytoplasm, Humans, Mutation, Benzoquinones, Lactams, Macrocyclic, Rats, alpha-Synuclein
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