1. Inhibition of the deubiquitinase USP8 corrects a Drosophila PINK1 model of mitochondria dysfunction
- Author
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Joy Chakraborty, Caterina Da Re, Luca Scorrano, Federico Caicci, Sophia von Stockum, Elena Marchesan, Vanni Ferrari, Alexander J. Whitworth, Paola Cusumano, Samantha Corrà, Lisa Locatello, Alvaro Sanchez-Martinez, Ildikò Szabò, Luigi Bubacco, Rodolfo Costa, Elena Ziviani, Maria B. Rasotto, Whitworth, Alex [0000-0002-1154-6629], and Apollo - University of Cambridge Repository
- Subjects
Male ,Dopamine ,Ubiquitin-Protein Ligases ,Health, Toxicology and Mutagenesis ,Longevity ,Down-Regulation ,PINK1 ,Plant Science ,Protein Serine-Threonine Kinases ,Mitochondrion ,Transfection ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Cell Line ,Deubiquitinating enzyme ,03 medical and health sciences ,0302 clinical medicine ,RNA interference ,Animals ,Drosophila Proteins ,Dimethyl Sulfoxide ,Gene Silencing ,Drosophila ,Research Articles ,030304 developmental biology ,0303 health sciences ,Ecology ,biology ,Dopaminergic Neurons ,Dopaminergic ,Membrane Proteins ,Parkinson Disease ,biology.organism_classification ,nervous system diseases ,Mitochondria ,Cell biology ,Drosophila melanogaster ,Phenotype ,mitochondrial fusion ,biology.protein ,Ubiquitin-Specific Proteases ,030217 neurology & neurosurgery ,Function (biology) ,Research Article ,Signal Transduction - Abstract
Aberrant mitochondrial dynamics contribute to disease conditions. Genetic and pharmacological inhibition of USP8 ameliorates mitochondrial phenotypes deriving from loss of function of Drosophila PINK1 and Parkin., Aberrant mitochondrial dynamics disrupts mitochondrial function and contributes to disease conditions. A targeted RNA interference screen for deubiquitinating enzymes (DUBs) affecting protein levels of multifunctional mitochondrial fusion protein Mitofusin (MFN) identified USP8 prominently influencing MFN levels. Genetic and pharmacological inhibition of USP8 normalized the elevated MFN protein levels observed in PINK1 and Parkin-deficient models. This correlated with improved mitochondrial function, locomotor performance and life span, and prevented dopaminergic neurons loss in Drosophila PINK1 KO flies. We identified a novel target antagonizing pathologically elevated MFN levels, mitochondrial dysfunction, and dopaminergic neuron loss of a Drosophila model of mitochondrial dysfunction.
- Published
- 2019
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