The HSP110/HSP70 disaggregation system generates spreading-competent toxic α-synuclein species.
EMBO J
; 39(13): e103954, 2020 07 01.
Article
em En
| MEDLINE
| ID: mdl-32449565
ABSTRACT
The accumulation and prion-like propagation of α-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 α-synuclein fibrils in vitro, but its physiological effects on α-synuclein toxicity are unknown. Here, we depleted Caenorhabditis elegans HSP-110 and monitored the consequences on α-synuclein-related pathological phenotypes such as misfolding, intercellular spreading, and toxicity in C. elegans in vivo models. 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 α-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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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Caenorhabditis elegans
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Proteínas de Choque Térmico HSP70
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Proteínas de Caenorhabditis elegans
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Proteínas de Choque Térmico HSP110
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Alfa-Sinucleína
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Agregados Proteicos
Limite:
Animals
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article