Inhibition of the deubiquitinase USP8 corrects a Drosophila PINK1 model of mitochondria dysfunction

Autor: 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
Přispěvatelé: Whitworth, Alex [0000-0002-1154-6629], Apollo - University of Cambridge Repository
Rok vydání: 2019
Předmět:
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
Zdroj: Life Science Alliance
ISSN: 2575-1077
DOI: 10.26508/lsa.201900392
Popis: 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.
Databáze: OpenAIRE
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