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Decreased Sirtuin Deacetylase Activity in LRRK2 G2019S iPSC-Derived Dopaminergic Neurons

Mitochondrial changes have long been implicated in the pathogenesis of Parkinson's disease (PD). The glycine to serine mutation (G2019S) in leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause for PD and has been shown to impair mitochondrial function and morphology in multiple...

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Detalles Bibliográficos
Autores principales: Schwab, Andrew J., Sison, Samantha L., Meade, Michael R., Broniowska, Katarzyna A., Corbett, John A., Ebert, Allison D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785678/
https://www.ncbi.nlm.nih.gov/pubmed/29129681
http://dx.doi.org/10.1016/j.stemcr.2017.10.010
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author Schwab, Andrew J.
Sison, Samantha L.
Meade, Michael R.
Broniowska, Katarzyna A.
Corbett, John A.
Ebert, Allison D.
author_facet Schwab, Andrew J.
Sison, Samantha L.
Meade, Michael R.
Broniowska, Katarzyna A.
Corbett, John A.
Ebert, Allison D.
author_sort Schwab, Andrew J.
collection PubMed
description Mitochondrial changes have long been implicated in the pathogenesis of Parkinson's disease (PD). The glycine to serine mutation (G2019S) in leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause for PD and has been shown to impair mitochondrial function and morphology in multiple model systems. We analyzed mitochondrial function in LRRK2 G2019S induced pluripotent stem cell (iPSC)-derived neurons to determine whether the G2019S mutation elicits similar mitochondrial deficits among central and peripheral nervous system neuron subtypes. LRRK2 G2019S iPSC-derived dopaminergic neuron cultures displayed unique abnormalities in mitochondrial distribution and trafficking, which corresponded to reduced sirtuin deacetylase activity and nicotinamide adenine dinucleotide levels despite increased sirtuin levels. These data indicate that mitochondrial deficits in the context of LRRK2 G2019S are not a global phenomenon and point to distinct sirtuin and bioenergetic deficiencies intrinsic to dopaminergic neurons, which may underlie dopaminergic neuron loss in PD.
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spelling pubmed-57856782018-01-29 Decreased Sirtuin Deacetylase Activity in LRRK2 G2019S iPSC-Derived Dopaminergic Neurons Schwab, Andrew J. Sison, Samantha L. Meade, Michael R. Broniowska, Katarzyna A. Corbett, John A. Ebert, Allison D. Stem Cell Reports Article Mitochondrial changes have long been implicated in the pathogenesis of Parkinson's disease (PD). The glycine to serine mutation (G2019S) in leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause for PD and has been shown to impair mitochondrial function and morphology in multiple model systems. We analyzed mitochondrial function in LRRK2 G2019S induced pluripotent stem cell (iPSC)-derived neurons to determine whether the G2019S mutation elicits similar mitochondrial deficits among central and peripheral nervous system neuron subtypes. LRRK2 G2019S iPSC-derived dopaminergic neuron cultures displayed unique abnormalities in mitochondrial distribution and trafficking, which corresponded to reduced sirtuin deacetylase activity and nicotinamide adenine dinucleotide levels despite increased sirtuin levels. These data indicate that mitochondrial deficits in the context of LRRK2 G2019S are not a global phenomenon and point to distinct sirtuin and bioenergetic deficiencies intrinsic to dopaminergic neurons, which may underlie dopaminergic neuron loss in PD. Elsevier 2017-11-09 /pmc/articles/PMC5785678/ /pubmed/29129681 http://dx.doi.org/10.1016/j.stemcr.2017.10.010 Text en © 2017 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Schwab, Andrew J.
Sison, Samantha L.
Meade, Michael R.
Broniowska, Katarzyna A.
Corbett, John A.
Ebert, Allison D.
Decreased Sirtuin Deacetylase Activity in LRRK2 G2019S iPSC-Derived Dopaminergic Neurons
title Decreased Sirtuin Deacetylase Activity in LRRK2 G2019S iPSC-Derived Dopaminergic Neurons
title_full Decreased Sirtuin Deacetylase Activity in LRRK2 G2019S iPSC-Derived Dopaminergic Neurons
title_fullStr Decreased Sirtuin Deacetylase Activity in LRRK2 G2019S iPSC-Derived Dopaminergic Neurons
title_full_unstemmed Decreased Sirtuin Deacetylase Activity in LRRK2 G2019S iPSC-Derived Dopaminergic Neurons
title_short Decreased Sirtuin Deacetylase Activity in LRRK2 G2019S iPSC-Derived Dopaminergic Neurons
title_sort decreased sirtuin deacetylase activity in lrrk2 g2019s ipsc-derived dopaminergic neurons
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785678/
https://www.ncbi.nlm.nih.gov/pubmed/29129681
http://dx.doi.org/10.1016/j.stemcr.2017.10.010
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