Decreased Sirtuin Deacetylase Activity in LRRK2 G2019S iPSC-Derived Dopaminergic Neurons. Stem Cell Reports 2017 Dec 12;9(6):1839-1852
Date
11/14/2017Pubmed ID
29129681Pubmed Central ID
PMC5785678DOI
10.1016/j.stemcr.2017.10.010Scopus ID
2-s2.0-85033362137 (requires institutional sign-in at Scopus site) 73 CitationsAbstract
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.
Author List
Schwab AJ, Sison SL, Meade MR, Broniowska KA, Corbett JA, Ebert ADAuthors
John A. Corbett PhD Chair, Professor in the Biochemistry department at Medical College of WisconsinAllison D. Ebert PhD Center Director, Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsDisease Models, Animal
Dopaminergic Neurons
Group III Histone Deacetylases
Humans
Induced Pluripotent Stem Cells
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Mitochondria
Mutation
Neurites
Parkinson Disease
