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 |
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Article number | 101375 |
Journal | iScience |
Volume | 23 |
Issue number | 8 |
DOIs | |
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