Mitochondrial Dynamics in an LRRK2 G2019S Model of Parkinson's Disease

Date
2019
Authors
Duginski, Christine
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Abstract

Despite decades of research, Parkinson's disease (PD) remains incurable and no treatment even slows the progression of the disease. The G2019S mutation in Leucine Rich Repeat Kinase 2 (LRRK2) is the leading cause of familial PD. Animal models have not fully recapitulated the human PD phenotype and therefore we used human induced pluripotent stem cells (iPSCs) to study the effects of mutant and wildtype LRRK2 on dopaminergic differentiation in vitro. We also examined the effect on expression of mitochondrial genes during differentiation as well as mitochondrial translocation in fully differentiated dopaminergic neurons. To distinguish the effects of PD from those of G2019S LRRK2 we included samples from subjects carrying the mutation with and without PD. We confirmed dopaminergic differentiation using qRT-PCR and immunocytochemistry. We find key dopaminergic (LMX1A, FOXA2, OTX2) and mitochondrial genes (DNM1L,FIS1, MFN1,OPA1) are expressed at lower levels in the affected line at day 11 of differentiation. No difference was observed between the unaffected line carrying the mutation and the wildtype line suggesting that this result is dependent on the PD status and not the LRRK2 mutation. Conversely, when we examined mitochondrial translocation velocity the two mutant cell lines had a small but significant increase in velocity when compared to the wildtype line and were not different from one another. Mitochondrial translocation is an important part of regulating mitochondrial health and our results may suggest a larger defect observed in the mitochondria of cells containing the G2019S mutation in LRRK2.

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Keywords
Dopamine, LRRK2 G2019S, Mitochondria, Parkinson's Disease, Stem Cells, Velocity
Citation
Department
Integrative Biology