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

Pedro Fernandez-Funez; Jonatan Sanchez-Garcia; Lorena De Mena; Yan Zhang; Yona Levites; Swati Khare; Todd E. Golde; Diego E. Rincon-Limas

doi:10.1073/pnas.1608045113

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

Pedro Fernandez-Funez, Jonatan Sanchez-Garcia, Lorena De Mena, Yan Zhang, Yona Levites, Swati Khare, Todd E. Golde, Diego E. Rincon-Limas

Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

50 Scopus citations

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.

Original language	English (US)
Pages (from-to)	E5212-E5221
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	113
Issue number	35
DOIs	https://doi.org/10.1073/pnas.1608045113
State	Published - Aug 30 2016

Bibliographical note

Funding Information:
We thank Shailaja Emani for technical assistance, Nancy Bonini (University of Pennsylvania) for the human HSPA1L construct and flies, Mary Konsolaki (Rutgers University) for the GMR-Aβ42(4×) flies, Ben-Zion Shilo (Weizmann Institute for Science) for the secGFP flies, Bradley Hyman (Massachusetts General Hospital) for the HEK293 cells/split-luciferase Aβ42, Amit Singh (University of Dayton) for the optimized TUNEL protocol, Hermann Steller (Rockefeller University) for the anti-Hsc3 antibody, the Bloomington Drosophila Stock Center (NIH P40OD018537) for fly strains, and the Developmental Studies Hybridoma Bank for antibodies. This work was supported by NIH Grants DP2 OD002721-01 (to P.F.-F.) and R21NS081356 (to D.E.R.-L.) and a McKnight Brain Institute Research Development Award (to P.F.-F. and D.E.R.-L.).

Keywords

Amyloid-β
Drosophila
Engineered chaperones
Hsp70
Neuroprotections

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title = "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.",

keywords = "Amyloid-β, Drosophila, Engineered chaperones, Hsp70, Neuroprotections",

author = "Pedro Fernandez-Funez and Jonatan Sanchez-Garcia and {De Mena}, Lorena and Yan Zhang and Yona Levites and Swati Khare and Golde, {Todd E.} and Rincon-Limas, {Diego E.}",

note = "Funding Information: We thank Shailaja Emani for technical assistance, Nancy Bonini (University of Pennsylvania) for the human HSPA1L construct and flies, Mary Konsolaki (Rutgers University) for the GMR-Aβ42(4×) flies, Ben-Zion Shilo (Weizmann Institute for Science) for the secGFP flies, Bradley Hyman (Massachusetts General Hospital) for the HEK293 cells/split-luciferase Aβ42, Amit Singh (University of Dayton) for the optimized TUNEL protocol, Hermann Steller (Rockefeller University) for the anti-Hsc3 antibody, the Bloomington Drosophila Stock Center (NIH P40OD018537) for fly strains, and the Developmental Studies Hybridoma Bank for antibodies. This work was supported by NIH Grants DP2 OD002721-01 (to P.F.-F.) and R21NS081356 (to D.E.R.-L.) and a McKnight Brain Institute Research Development Award (to P.F.-F. and D.E.R.-L.).",

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AU - Fernandez-Funez, Pedro

AU - Sanchez-Garcia, Jonatan

AU - De Mena, Lorena

AU - Zhang, Yan

AU - Levites, Yona

AU - Khare, Swati

AU - Golde, Todd E.

AU - Rincon-Limas, Diego E.

N1 - Funding Information: We thank Shailaja Emani for technical assistance, Nancy Bonini (University of Pennsylvania) for the human HSPA1L construct and flies, Mary Konsolaki (Rutgers University) for the GMR-Aβ42(4×) flies, Ben-Zion Shilo (Weizmann Institute for Science) for the secGFP flies, Bradley Hyman (Massachusetts General Hospital) for the HEK293 cells/split-luciferase Aβ42, Amit Singh (University of Dayton) for the optimized TUNEL protocol, Hermann Steller (Rockefeller University) for the anti-Hsc3 antibody, the Bloomington Drosophila Stock Center (NIH P40OD018537) for fly strains, and the Developmental Studies Hybridoma Bank for antibodies. This work was supported by NIH Grants DP2 OD002721-01 (to P.F.-F.) and R21NS081356 (to D.E.R.-L.) and a McKnight Brain Institute Research Development Award (to P.F.-F. and D.E.R.-L.).

PY - 2016/8/30

Y1 - 2016/8/30

N2 - 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.

AB - 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.

KW - Amyloid-β

KW - Drosophila

KW - Engineered chaperones

KW - Hsp70

KW - Neuroprotections

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JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 35

ER -

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

Abstract

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