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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 influenci...

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Autores principales: von Stockum, Sophia, Sanchez-Martinez, Alvaro, Corrà, Samantha, Chakraborty, Joy, Marchesan, Elena, Locatello, Lisa, Da Rè, Caterina, Cusumano, Paola, Caicci, Federico, Ferrari, Vanni, Costa, Rodolfo, Bubacco, Luigi, Rasotto, Maria Berica, Szabo, Ildiko, Whitworth, Alexander J, Scorrano, Luca, Ziviani, Elena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Life Science Alliance LLC 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467245/
https://www.ncbi.nlm.nih.gov/pubmed/30988163
http://dx.doi.org/10.26508/lsa.201900392
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author von Stockum, Sophia
Sanchez-Martinez, Alvaro
Corrà, Samantha
Chakraborty, Joy
Marchesan, Elena
Locatello, Lisa
Da Rè, Caterina
Cusumano, Paola
Caicci, Federico
Ferrari, Vanni
Costa, Rodolfo
Bubacco, Luigi
Rasotto, Maria Berica
Szabo, Ildiko
Whitworth, Alexander J
Scorrano, Luca
Ziviani, Elena
author_facet von Stockum, Sophia
Sanchez-Martinez, Alvaro
Corrà, Samantha
Chakraborty, Joy
Marchesan, Elena
Locatello, Lisa
Da Rè, Caterina
Cusumano, Paola
Caicci, Federico
Ferrari, Vanni
Costa, Rodolfo
Bubacco, Luigi
Rasotto, Maria Berica
Szabo, Ildiko
Whitworth, Alexander J
Scorrano, Luca
Ziviani, Elena
author_sort von Stockum, Sophia
collection PubMed
description 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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spelling pubmed-64672452019-04-17 Inhibition of the deubiquitinase USP8 corrects a Drosophila PINK1 model of mitochondria dysfunction von Stockum, Sophia Sanchez-Martinez, Alvaro Corrà, Samantha Chakraborty, Joy Marchesan, Elena Locatello, Lisa Da Rè, Caterina Cusumano, Paola Caicci, Federico Ferrari, Vanni Costa, Rodolfo Bubacco, Luigi Rasotto, Maria Berica Szabo, Ildiko Whitworth, Alexander J Scorrano, Luca Ziviani, Elena Life Sci Alliance Research Articles 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. Life Science Alliance LLC 2019-04-15 /pmc/articles/PMC6467245/ /pubmed/30988163 http://dx.doi.org/10.26508/lsa.201900392 Text en © 2019 von Stockum et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Articles
von Stockum, Sophia
Sanchez-Martinez, Alvaro
Corrà, Samantha
Chakraborty, Joy
Marchesan, Elena
Locatello, Lisa
Da Rè, Caterina
Cusumano, Paola
Caicci, Federico
Ferrari, Vanni
Costa, Rodolfo
Bubacco, Luigi
Rasotto, Maria Berica
Szabo, Ildiko
Whitworth, Alexander J
Scorrano, Luca
Ziviani, Elena
Inhibition of the deubiquitinase USP8 corrects a Drosophila PINK1 model of mitochondria dysfunction
title Inhibition of the deubiquitinase USP8 corrects a Drosophila PINK1 model of mitochondria dysfunction
title_full Inhibition of the deubiquitinase USP8 corrects a Drosophila PINK1 model of mitochondria dysfunction
title_fullStr Inhibition of the deubiquitinase USP8 corrects a Drosophila PINK1 model of mitochondria dysfunction
title_full_unstemmed Inhibition of the deubiquitinase USP8 corrects a Drosophila PINK1 model of mitochondria dysfunction
title_short Inhibition of the deubiquitinase USP8 corrects a Drosophila PINK1 model of mitochondria dysfunction
title_sort inhibition of the deubiquitinase usp8 corrects a drosophila pink1 model of mitochondria dysfunction
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467245/
https://www.ncbi.nlm.nih.gov/pubmed/30988163
http://dx.doi.org/10.26508/lsa.201900392
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