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
Affiliations
Lital Dabool
Department of Human Biology, Faculty of Natural Sciences, University of Haifa, 199 Aba Khoushy Avenue, Mount Carmel, Haifa 34988-38, Israel; The Rappaport Family Institute for Research in the Medical Sciences, Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel
Ketty Hakim-Mishnaevski
Department of Human Biology, Faculty of Natural Sciences, University of Haifa, 199 Aba Khoushy Avenue, Mount Carmel, Haifa 34988-38, Israel
Liza Juravlev
Department of Human Biology, Faculty of Natural Sciences, University of Haifa, 199 Aba Khoushy Avenue, Mount Carmel, Haifa 34988-38, Israel
Naama Flint-Brodsly
Department of Human Biology, Faculty of Natural Sciences, University of Haifa, 199 Aba Khoushy Avenue, Mount Carmel, Haifa 34988-38, Israel
Silvia Mandel
The Rappaport Family Institute for Research in the Medical Sciences, Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel
Estee Kurant
Department of Human Biology, Faculty of Natural Sciences, University of Haifa, 199 Aba Khoushy Avenue, Mount Carmel, Haifa 34988-38, Israel; The Rappaport Family Institute for Research in the Medical Sciences, Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel; Corresponding author
Summary: 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.
