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PINK1/Parkin Pathway Activation for Mitochondrial Quality Control – Which Is the Best Molecular Target for Therapy?

There has been long-term interest in drugging the PINK1-Parkin pathway with therapeutics as a treatment for Parkinson’s disease (PD). Despite significant structural data on Parkin as well as the PINK1 kinase and the multiple conformational changes it undergoes, activation of these targets is non-tri...

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Autor principal: Silvian, Laura F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9215347/
https://www.ncbi.nlm.nih.gov/pubmed/35754955
http://dx.doi.org/10.3389/fnagi.2022.890823
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author Silvian, Laura F.
author_facet Silvian, Laura F.
author_sort Silvian, Laura F.
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description There has been long-term interest in drugging the PINK1-Parkin pathway with therapeutics as a treatment for Parkinson’s disease (PD). Despite significant structural data on Parkin as well as the PINK1 kinase and the multiple conformational changes it undergoes, activation of these targets is non-trivial. This review highlights small molecule screening results that suggests that activation of Parkin biochemically does not necessarily translate to activation of Parkin within cells. There are also issues with activation of PINK1 with kinetin analogs, which do not appear to rescue rodent models of PD. The counter-measure of activating the mitophagy pathway with deubiquitinase (DUB) inhibitors such as USP30 inhibitors is progressing in the clinic for kidney disease and the proof of biology for this target will be tested in these trials. An alternative mechanism of activating Parkin in response to oxidative stress via Parkin phosphorylation by the AMPK-ULK1 pathway may be a simpler way to lower the energy barrier Parkin activation.
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spelling pubmed-92153472022-06-23 PINK1/Parkin Pathway Activation for Mitochondrial Quality Control – Which Is the Best Molecular Target for Therapy? Silvian, Laura F. Front Aging Neurosci Neuroscience There has been long-term interest in drugging the PINK1-Parkin pathway with therapeutics as a treatment for Parkinson’s disease (PD). Despite significant structural data on Parkin as well as the PINK1 kinase and the multiple conformational changes it undergoes, activation of these targets is non-trivial. This review highlights small molecule screening results that suggests that activation of Parkin biochemically does not necessarily translate to activation of Parkin within cells. There are also issues with activation of PINK1 with kinetin analogs, which do not appear to rescue rodent models of PD. The counter-measure of activating the mitophagy pathway with deubiquitinase (DUB) inhibitors such as USP30 inhibitors is progressing in the clinic for kidney disease and the proof of biology for this target will be tested in these trials. An alternative mechanism of activating Parkin in response to oxidative stress via Parkin phosphorylation by the AMPK-ULK1 pathway may be a simpler way to lower the energy barrier Parkin activation. Frontiers Media S.A. 2022-06-08 /pmc/articles/PMC9215347/ /pubmed/35754955 http://dx.doi.org/10.3389/fnagi.2022.890823 Text en Copyright © 2022 Silvian. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Silvian, Laura F.
PINK1/Parkin Pathway Activation for Mitochondrial Quality Control – Which Is the Best Molecular Target for Therapy?
title PINK1/Parkin Pathway Activation for Mitochondrial Quality Control – Which Is the Best Molecular Target for Therapy?
title_full PINK1/Parkin Pathway Activation for Mitochondrial Quality Control – Which Is the Best Molecular Target for Therapy?
title_fullStr PINK1/Parkin Pathway Activation for Mitochondrial Quality Control – Which Is the Best Molecular Target for Therapy?
title_full_unstemmed PINK1/Parkin Pathway Activation for Mitochondrial Quality Control – Which Is the Best Molecular Target for Therapy?
title_short PINK1/Parkin Pathway Activation for Mitochondrial Quality Control – Which Is the Best Molecular Target for Therapy?
title_sort pink1/parkin pathway activation for mitochondrial quality control – which is the best molecular target for therapy?
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9215347/
https://www.ncbi.nlm.nih.gov/pubmed/35754955
http://dx.doi.org/10.3389/fnagi.2022.890823
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