Drosophila Skp1 Homologue SkpA Plays a Neuroprotective Role in Adult Brain

Lital Dabool; Ketty Hakim-Mishnaevski; Liza Juravlev; Naama Flint-Brodsly; Silvia Mandel; Estee Kurant

doi:10.1016/j.isci.2020.101375

Drosophila Skp1 Homologue SkpA Plays a Neuroprotective Role in Adult Brain

Lital Dabool, Ketty Hakim-Mishnaevski, Liza Juravlev, Naama Flint-Brodsly, Silvia Mandel, Estee Kurant

Department of Human Biology

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

Abstract

Skp1, a component of the ubiquitin E3 ligases, was found to be decreased in the brains of sporadic Parkinson's disease (PD) patients, and its overexpression prevented death of murine neurons in culture. Here we expose the neuroprotective role of the Drosophila skp1 homolog, skpA, in the adult brain. Neuronal knockdown of skpA leads to accumulation of ubiquitinated protein aggregates and loss of dopaminergic neurons accompanied by motor dysfunction and reduced lifespan. Conversely, neuronal overexpression of skpA reduces aggregate load, improves age-related motor decline, and prolongs lifespan. Moreover, SkpA rescues neurodegeneration in a Drosophila model of PD. We also show that a Drosophila homolog of FBXO7, the F Box protein, Nutcracker (Ntc), works in the same pathway with SkpA. However, skpA overexpression rescues ntc knockdown phenotype, suggesting that SkpA interacts with additional F box proteins in the adult brain neurons. Collectively, our study discloses Skp1/SkpA as a potential therapeutic target in neurodegenerative diseases.

Original language	English
Article number	101375
Journal	iScience
Volume	23
Issue number	8
DOIs	https://doi.org/10.1016/j.isci.2020.101375
State	Published - 21 Aug 2020

Bibliographical note

Funding Information:
We are grateful to E. Arama and O. Schuldiner (The Weizmann Institute of Science), H. Steller (Rockefeller University), U. Gaul (LMU), B. Mollereau (ENS de Lyon), VDRC, FlyORF, and the Bloomington Drosophila Stock Center for providing fly strains. We also thank the Kurant laboratory members for meaningful discussions. We gratefully acknowledge the financial support from the Israel Science Foundation (grant # 1872/15). L.D. K.HM. L.J. and N.FB. conducted the experiments; L.D. and E.K. designed and analyzed the experiments; S.M. advised on Skp1; and E.K. wrote the paper. The authors declare no competing interests.

Funding Information:
We are grateful to E. Arama and O. Schuldiner (The Weizmann Institute of Science), H. Steller (Rockefeller University), U. Gaul (LMU), B. Mollereau (ENS de Lyon), VDRC, FlyORF, and the Bloomington Drosophila Stock Center for providing fly strains. We also thank the Kurant laboratory members for meaningful discussions. We gratefully acknowledge the financial support from the Israel Science Foundation (grant # 1872/15 ).

Publisher Copyright:
© 2020 The Author(s)

Keywords

Behavioral Neuroscience
Cellular Neuroscience
Molecular Neuroscience

ASJC Scopus subject areas

General

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10.1016/j.isci.2020.101375

Cite this

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title = "Drosophila Skp1 Homologue SkpA Plays a Neuroprotective Role in Adult Brain",

abstract = "Skp1, a component of the ubiquitin E3 ligases, was found to be decreased in the brains of sporadic Parkinson's disease (PD) patients, and its overexpression prevented death of murine neurons in culture. Here we expose the neuroprotective role of the Drosophila skp1 homolog, skpA, in the adult brain. Neuronal knockdown of skpA leads to accumulation of ubiquitinated protein aggregates and loss of dopaminergic neurons accompanied by motor dysfunction and reduced lifespan. Conversely, neuronal overexpression of skpA reduces aggregate load, improves age-related motor decline, and prolongs lifespan. Moreover, SkpA rescues neurodegeneration in a Drosophila model of PD. We also show that a Drosophila homolog of FBXO7, the F Box protein, Nutcracker (Ntc), works in the same pathway with SkpA. However, skpA overexpression rescues ntc knockdown phenotype, suggesting that SkpA interacts with additional F box proteins in the adult brain neurons. Collectively, our study discloses Skp1/SkpA as a potential therapeutic target in neurodegenerative diseases.",

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author = "Lital Dabool and Ketty Hakim-Mishnaevski and Liza Juravlev and Naama Flint-Brodsly and Silvia Mandel and Estee Kurant",

note = "Funding Information: We are grateful to E. Arama and O. Schuldiner (The Weizmann Institute of Science), H. Steller (Rockefeller University), U. Gaul (LMU), B. Mollereau (ENS de Lyon), VDRC, FlyORF, and the Bloomington Drosophila Stock Center for providing fly strains. We also thank the Kurant laboratory members for meaningful discussions. We gratefully acknowledge the financial support from the Israel Science Foundation (grant # 1872/15). L.D. K.HM. L.J. and N.FB. conducted the experiments; L.D. and E.K. designed and analyzed the experiments; S.M. advised on Skp1; and E.K. wrote the paper. The authors declare no competing interests. Funding Information: We are grateful to E. Arama and O. Schuldiner (The Weizmann Institute of Science), H. Steller (Rockefeller University), U. Gaul (LMU), B. Mollereau (ENS de Lyon), VDRC, FlyORF, and the Bloomington Drosophila Stock Center for providing fly strains. We also thank the Kurant laboratory members for meaningful discussions. We gratefully acknowledge the financial support from the Israel Science Foundation (grant # 1872/15 ). Publisher Copyright: {\textcopyright} 2020 The Author(s)",

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AU - Hakim-Mishnaevski, Ketty

AU - Juravlev, Liza

AU - Flint-Brodsly, Naama

AU - Mandel, Silvia

AU - Kurant, Estee

N1 - Funding Information: We are grateful to E. Arama and O. Schuldiner (The Weizmann Institute of Science), H. Steller (Rockefeller University), U. Gaul (LMU), B. Mollereau (ENS de Lyon), VDRC, FlyORF, and the Bloomington Drosophila Stock Center for providing fly strains. We also thank the Kurant laboratory members for meaningful discussions. We gratefully acknowledge the financial support from the Israel Science Foundation (grant # 1872/15). L.D. K.HM. L.J. and N.FB. conducted the experiments; L.D. and E.K. designed and analyzed the experiments; S.M. advised on Skp1; and E.K. wrote the paper. The authors declare no competing interests. Funding Information: We are grateful to E. Arama and O. Schuldiner (The Weizmann Institute of Science), H. Steller (Rockefeller University), U. Gaul (LMU), B. Mollereau (ENS de Lyon), VDRC, FlyORF, and the Bloomington Drosophila Stock Center for providing fly strains. We also thank the Kurant laboratory members for meaningful discussions. We gratefully acknowledge the financial support from the Israel Science Foundation (grant # 1872/15 ). Publisher Copyright: © 2020 The Author(s)

PY - 2020/8/21

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N2 - Skp1, a component of the ubiquitin E3 ligases, was found to be decreased in the brains of sporadic Parkinson's disease (PD) patients, and its overexpression prevented death of murine neurons in culture. Here we expose the neuroprotective role of the Drosophila skp1 homolog, skpA, in the adult brain. Neuronal knockdown of skpA leads to accumulation of ubiquitinated protein aggregates and loss of dopaminergic neurons accompanied by motor dysfunction and reduced lifespan. Conversely, neuronal overexpression of skpA reduces aggregate load, improves age-related motor decline, and prolongs lifespan. Moreover, SkpA rescues neurodegeneration in a Drosophila model of PD. We also show that a Drosophila homolog of FBXO7, the F Box protein, Nutcracker (Ntc), works in the same pathway with SkpA. However, skpA overexpression rescues ntc knockdown phenotype, suggesting that SkpA interacts with additional F box proteins in the adult brain neurons. Collectively, our study discloses Skp1/SkpA as a potential therapeutic target in neurodegenerative diseases.

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Drosophila Skp1 Homologue SkpA Plays a Neuroprotective Role in Adult Brain

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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