Holdase activity of secreted Hsp70 masks amyloid-β42 neurotoxicity in Drosophila.

Abstract:

:Alzheimer's disease (AD) is the most prevalent of a large group of related proteinopathies for which there is currently no cure. Here, we used Drosophila to explore a strategy to block Aβ42 neurotoxicity through engineering of the Heat shock protein 70 (Hsp70), a chaperone that has demonstrated neuroprotective activity against several intracellular amyloids. To target its protective activity against extracellular Aβ42, we added a signal peptide to Hsp70. This secreted form of Hsp70 (secHsp70) suppresses Aβ42 neurotoxicity in adult eyes, reduces cell death, protects the structural integrity of adult neurons, alleviates locomotor dysfunction, and extends lifespan. SecHsp70 binding to Aβ42 through its holdase domain is neuroprotective, but its ATPase activity is not required in the extracellular space. Thus, the holdase activity of secHsp70 masks Aβ42 neurotoxicity by promoting the accumulation of nontoxic aggregates. Combined with other approaches, this strategy may contribute to reduce the burden of AD and other extracellular proteinopathies.

authors

Fernandez-Funez P,Sanchez-Garcia J,de Mena L,Zhang Y,Levites Y,Khare S,Golde TE,Rincon-Limas DE

doi

10.1073/pnas.1608045113

subject

Has Abstract

pub_date

2016-08-30 00:00:00

pages

E5212-21

issue

35

eissn

0027-8424

issn

1091-6490

pii

1608045113

journal_volume

113

pub_type

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