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

By H. N. Nguyen, B. Byers, B. Cord, A. Shcheglovitov, J. Byrne, Prachi Gujar, K. Kee, B. Schüle, R. Dolmetsch, W. Langston and 2 more. Cell Stem Cell, 2011

756 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/4c13143feb6dcf1004eb22bbf360e493d83f9817

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In Cellular and Molecular Neuroscience

1. M. Mouradian
2. V. Dias
3. E. Junn

In Molecular Biology

1. M. Mouradian
2. V. Dias
3. E. Junn

In Neurology

1. M. Mouradian
2. V. Dias
3. E. Junn

Citations in the corpus

• Human iPSC-based Modeling of Late-Onset Disease via Progerin-induced Aging (2013, neutral): “…reported phenotypes in cell types of uncertain relevance for PD such as neural stem cells (Liu et al., 2012b) or early biochemical phenotypes in mDA neurons without modeling the severe neurodegenerative features of the disease (Cooper et al., 2012; Nguyen et al., 2011; Seibler et al., 2011).”
• The Role of Oxidative Stress in Parkinson’s Disease (2013, background): “Over-expression of wild-type or mutant LRRK2 with enhanced kinase activity in various cell lines or primary neurons leads to mitochondrial fragmentation and dysfunction associated with increased ROS generation and increased susceptibility to H2O2 [149, 395, 396].”
• Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects (2015, neutral): “, 2011), reactive oxygen species (Mertens et al., 2013a; Nguyen et al., 2011; Reinhardt et al., 2013), or overexpression of disease- or aging-related mutant proteins to accelerate pathological processes in these otherwise rejuvenated neuronal cells (Koch et al.”