The HSP110/HSP70 disaggregation system generates spreading-competent toxic alpha-synuclein species
The accumulation and prion-like propagation of alpha-synuclein and other amyloidogenic proteins are associated with devastating neurodegenerative diseases. Metazoan heat shock protein HSP70 and its co-chaperones DNAJB1 and HSP110 constitute a disaggregation machinery that is able to disassemble alph...
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| Main Authors: | , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
25 May 2020
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| In: |
The EMBO journal
Year: 2020, Volume: 39, Issue: 13 |
| ISSN: | 1460-2075 |
| DOI: | 10.15252/embj.2019103954 |
| Online Access: | Resolving-System, kostenfrei, Volltext: https://doi.org/10.15252/embj.2019103954
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| Author Notes: | Jessica Tittelmeier, Carl Alexander Sandhof, Heidrun Maja Ries, Silke Druffel-Augustin, Axel Mogk, Bernd Bukau & Carmen Nussbaum-Krammer |
| Summary: | The accumulation and prion-like propagation of alpha-synuclein and other amyloidogenic proteins are associated with devastating neurodegenerative diseases. Metazoan heat shock protein HSP70 and its co-chaperones DNAJB1 and HSP110 constitute a disaggregation machinery that is able to disassemble alpha-synuclein fibrilsin vitro, but its physiological effects on alpha-synuclein toxicity are unknown. Here, we depletedCaenorhabditis elegansHSP-110 and monitored the consequences on alpha-synuclein-related pathological phenotypes such as misfolding, intercellular spreading, and toxicity inC. elegans in vivomodels. Depletion of HSP-110 impaired HSP70 disaggregation activity, prevented resolubilization of amorphous aggregates, and compromised the overall cellular folding capacity. At the same time, HSP-110 depletion reduced alpha-synuclein foci formation, cell-to-cell transmission, and toxicity. These data demonstrate that the HSP70 disaggregation activity constitutes a double-edged sword, as it is essential for maintaining cellular proteostasis but also involved in the generation of toxic amyloid-type protein species. |
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| Item Description: | Gesehen am 30.07.2020 |
| Physical Description: | Online Resource |
| ISSN: | 1460-2075 |
| DOI: | 10.15252/embj.2019103954 |