Ziviani 2016 Abstract Mito Xmas Meeting Innsbruck

Playing hide and seek: inhibition of the Parkin-antagonizing deubiquitinase USP8 corrects a Drosophila PINK1 mutant model of Parkinson’s disease.

Link:

von Stockum S, Sanchez-Martinez A, Nardin A, Chakraborty J, Schrepfer E, Ferrari V, Da Re C, Cusumano P, Costa R, Bubacco L, Whitworth AJ, Scorrano L, Ziviani E (2016)

Event: Mito Xmas Meeting 2016 Innsbruck AT

During mitophagy, impaired in genetic Parkinson’s disease (PD), the kinase PINK1 recruits the E3 ubiquitin ligase Parkin to damaged mitochondria. Increased Parkin levels correct PINK1 deficient Drosophila PD models, suggesting that targeting the Parkin-opposing deubiquitination enzymes (DUBs) can yield the same result. Here we show that genetic and pharmacological inhibition of the Parkin-opposing DUB USP8 rescues a Drosophila model of PD. A targeted RNA interference screening for DUBs antagonizing Parkin ubiquitination of its key mitochondrial target Mitofusin (MFN) identified six DUBs among which USP8 caught our attention. Biochemical and functional analyses indicated that USP8 impinges on mitochondria dysfunction via Parkin. In vivo, genetic or pharmacological inhibition of USP8 corrected mitochondrial dysfunction and locomotor performance in a Drosophila PINK1 mutant model of PD, by impinging on the numerous MFN functions that in the fruit fly include both promotion of fusion and ER-mitochondria crosstalk. Our data identify a novel therapeutic target antagonizing pathologic symptoms in a model of PD.

Labels: MiParea: mtDNA;mt-genetics, Pharmacology;toxicology  Pathology: Parkinson's 

Organism: Drosophila 

Event: A2, Oral, Review 

Affiliations

von Stockum S(1,2), Sanchez-Martinez A(3,4), Nardin A(1), Chakraborty J(1), Schrepfer E(1,5), Ferrari V(1), Da Rè C(1,6), Cusumano P(1,6), Costa R(1,6), Bubacco L(1), Whitworth AJ(3,4), Scorrano L(1,5), Ziviani E(1,2)

1. Dept Biol, Univ Padova, Italy.

2 Ist IRCCS San Camillo, Venezia, Italy. 3 MRC Centre Developm Biomedical Genetics, Sheffield, UK. 4 Dept Biomedical Sc, Univ Sheffield, UK. 5 Dulbecco-Telethon Inst, Venetian Inst Molecular Medicine, Padova, Italy. 6 Neurogenetics Behavior Drosophila Lab, Dept Biology, Univ Padova, Italy.