LRRK2 Mutant iPSC-Derived DA Neurons Demonstrate Increased Susceptibility to Oxidative Stress

Abstract

SUMMARY Studies of Parkinson’s disease (PD) have been greatly hindered by lack of access to affected human dopaminergic (DA) neurons. Here, we report generation of induced pluripotent stem cells that carry the p.G2019S mutation (G2019S-iPSCs) in the Leucine-Rich Repeat Kinase-2 (LRRK2) gene, the most common PD-related mutation. We demonstrate that these G2019S-iPSCs were able to differentiate into DA neurons and showed increased expression of key oxidative stress response genes and α-synuclein protein. Moreover, G2019S-mutant DA neurons were more sensitive to caspase-3 activation, caused by exposure to hydrogen peroxide, MG-132, and 6-hydroxydopamine, compared to unaffected DA neurons. These findings suggest that G2019S-iPSC-derived DA neurons exhibit early phenotypes linked to PD. Due to high penetrance of the LRRK2 mutation and its clinical resemblance to sporadic PD, these neurons may provide a valuable platform for identification of novel pharmacological agents and diagnostics for modeling and alleviation of a subset of disease phenotypes.

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

“…In addition, dopaminergic neurons derived from G2019SͲiPS cells showed an increase of key oxidative stress response genes and pathogenomic accumulation of alphaͲ syn [212].…”

“…Furthermore, impaired mitochondrial function and an increased susceptibility to apoptosis were observed in ex vivo models of fibroblasts from PD patients carrying the G2019S mutation in the LRRK2 gene or based on induced pluripotent stem (iPS) cells that carry the G2019S mutation [211,212]. In addition, dopaminergic neurons derived from G2019SͲiPS cells showed an increase of key oxidative stress response genes and pathogenomic accumulation of alphaͲ syn [212].…”

Reprint of: Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

“…Furthermore, impaired mitochondrial function and an increased susceptibility to apoptosis were observed in ex vivo models of fibroblasts from PD patients carrying the G2019S mutation in the LRRK2 gene or based on induced pluripotent stem (iPS) cells that carry the G2019S mutation [211,212]. In addition, dopaminergic neurons derived from G2019S-iPS cells showed an increase in key oxidative stress response genes and pathogenomic accumulation of a-syn [212].…”

iPSCs and small molecules: a reciprocal effort towards better approaches for drug discovery

“…iPSCs have been established and used for in vitro disease modeling for two types of familial PD. iPSCs carrying the mutation in the gene encoding leucine-rich repeat kinase 2 (LRRK2), the most common cause of familial PD, were derived by Nguyen et al [30] . The iPSC-derived dopaminergic neurons displayed increased α-synuclein level and sensitivity towards environmental stress.…”