USP8

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Ubiquitin carboxyl-terminal hydrolase 8 (EC 3.4.19.12) (Deubiquitinating enzyme 8) (Ubiquitin isopeptidase Y) (hUBPy) (Ubiquitin thioesterase 8) (Ubiquitin-specific-processing protease 8) [KIAA0055] [UBPY]

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

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 [i]Drosophila[/i] PINK1 KO flies. We identified a novel target antagonizing pathologically elevated MFN levels, mitochondrial dysfunction, and dopaminergic neuron loss of a [i]Drosophila[/i] model of mitochondrial dysfunction.

MeSH Terms

  • Animals
  • Cell Line
  • Dimethyl Sulfoxide
  • Dopamine
  • Dopaminergic Neurons
  • Down-Regulation
  • Drosophila
  • Drosophila Proteins
  • Drosophila melanogaster
  • Gene Silencing
  • Longevity
  • Male
  • Membrane Proteins
  • Mitochondria
  • Parkinson Disease
  • Phenotype
  • Protein-Serine-Threonine Kinases
  • Signal Transduction
  • Transfection
  • Ubiquitin-Protein Ligases
  • Ubiquitin-Specific Proteases