2. Academic Validation
  3. Inhibition of the deubiquitinase USP8 corrects a Drosophila PINK1 model of mitochondria dysfunction

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

  • Life Sci Alliance. 2019 Apr 15;2(2):e201900392. doi: 10.26508/lsa.201900392.
Sophia von Stockum 1,  Alvaro Sanchez-Martinez 2,  Samantha Corrà 3 4,  Joy Chakraborty 3,  Elena Marchesan 1,  Lisa Locatello 3,  Caterina Da Rè 3 4,  Paola Cusumano 3 4,  Federico Caicci 3,  Vanni Ferrari 3,  Rodolfo Costa 3 4,  Luigi Bubacco 3,  Maria Berica Rasotto 3,  Ildiko Szabo 3,  Alexander J Whitworth 2,  Luca Scorrano 3 5,  Elena Ziviani 6 3
Affiliations

Affiliations

  • 1 Fondazione Ospedale San Camillo, IRCCS, Venezia, Italy.
  • 2 MRC Mitochondrial Biology Unit, Cambridge Biomedical Campus, Cambridge, UK.
  • 3 Department of Biology, University of Padova, Padova, Italy.
  • 4 Neurogenetics and Behavior of Drosophila Lab, Department of Biology, University of Padova, Padova, Italy.
  • 5 Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Padova, Italy.
  • 6 Fondazione Ospedale San Camillo, IRCCS, Venezia, Italy elena.ziviani@unipd.it.
PMID: 30988163 DOI: 10.26508/lsa.201900392
Abstract

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.

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