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

Abstract

SummaryMitochondrial 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.

Induced pluripotent stem cell‐based modeling of mutant LRRK2‐associated Parkinson's disease

“…The authors found increased expression of sirtuins, a family of nicotinamide adenine dinucleotide (NAD) + ‐dependent protein deacetylases involved in mitochondrial metabolism, but a decrease in deacetylase activity and complex III levels. LRRK2 kinase inhibitor treatment was not sufficient to normalize levels of sirtuins in LRRK2 G2019S mesDA neurons (Schwab et al., ). Interestingly, the authors could not observe these phenotypes in iPSC‐derived peripheral neurons, indicating neuronal subtype‐specific susceptibility.…”

“…Interestingly, the authors could not observe these phenotypes in iPSC‐derived peripheral neurons, indicating neuronal subtype‐specific susceptibility. Moreover, LRRK2 G2019S neurons were shown to display decreased ATP content (Schwab et al., ; Su & Qi, ), accompanied by a decrease in mitochondrial membrane potential (Hsieh et al., ; Su & Qi, ). Both findings were also observed in other PD models in SNCA trp and mutant OPA1 neural progenitor cells (NPCs) (Flierl et al., ; Iannielli et al., ).…”

“…The results are ambiguous, underscoring the complexity of this cellular trait. Su and Qi reported shortened mitochondrial length in mesDA neurons carrying the LRRK2 G2019S variant, and Schwab and colleagues revealed a reduced mitochondrial distribution in neurites (Schwab et al., ; Su & Qi, ). In contrast, Hsieh et al.…”

Mitochondrial dysfunction and oxidative stress in induced pluripotent stem cell models of Parkinson's disease

“…It has been shown that there is an increase in SNCA transcription in LRRK2‐G2019S mutant neurons (Nguyen et al., ) but other groups showed no upregulation of SNCA (Reinhardt et al., 2013; Sanchez‐Danes et al., ). It has been reported that dopaminergic neurons derived from LRRK2 G2019S IPSCs showed abnormal mitochondrial trafficking and distribution(Schwab et al., ). This correlated to reduced activity of sirtuin deacetylase and low levels of nicotinamide adenine dinucleotide but sirtuin levels were high.…”

“…An increase in bidirectional mobility of mitochondria in neurons from LRRK2 G2019S PD patients was also reported as compared to neurons derived from healthy controls (Cooper et al., ). It has been reported that dopaminergic neurons derived from LRRK2 G2019S IPSC demonstrate abnormal mitochondrial trafficking and distribution(Schwab et al., ). This correlated to reduced activity of sirtuin deacetylase and low levels of nicotinamide adenine dinucleotide but sirtuin levels were high.…”