LRRK2 mutations cause mitochondrial DNA damage in iPSC-derived neural cells from Parkinson's disease patients: Reversal by gene correction

• Published in: Neurobiology of disease Vol. 62; pp. 381 - 386
• Main Authors: Sanders, Laurie H., Laganière, Josée, Cooper, Oliver, Mak, Sally K., Vu, B. Joseph, Huang, Y. Anne, Paschon, David E., Vangipuram, Malini, Sundararajan, Ramya, Urnov, Fyodor D., Langston, J. William, Gregory, Philip D., Zhang, H. Steve, Greenamyre, J. Timothy, Isacson, Ole, Schüle, Birgitt
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2014; Elsevier
• Subjects: Adult; Aged; DNA Damage; DNA Repair; DNA, Mitochondrial - genetics; DNA, Mitochondrial - metabolism; Female; Humans; Induced Pluripotent Stem Cells - metabolism; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; LRRK2; Male; Middle Aged; Mitochondrial DNA damage; Mutation; Neural Stem Cells - metabolism; Neurology; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson's disease; Protein-Serine-Threonine Kinases - genetics; Stem cells; Targeted Gene Repair; Zinc Fingers; Parkinson's disease; LRRK2; Mitochondrial DNA damage; Stem cells
• ISSN: 0969-9961; 1095-953X; 1095-953X
• DOI: 10.1016/j.nbd.2013.10.013

Parkinson's disease associated mutations in leucine rich repeat kinase 2 (LRRK2) impair mitochondrial function and increase the vulnerability of induced pluripotent stem cell (iPSC)-derived neural cells from patients to oxidative stress. Since mitochondrial DNA (mtDNA) damage can compromise mitochondrial function, we examined whether LRRK2 mutations can induce damage to the mitochondrial genome. We found greater levels of mtDNA damage in iPSC-derived neural cells from patients carrying homozygous or heterozygous LRRK2 G2019S mutations, or at-risk individuals carrying the heterozygous LRRK2 R1441C mutation, than in cells from unrelated healthy subjects who do not carry LRRK2 mutations. After zinc finger nuclease-mediated repair of the LRRK2 G2019S mutation in iPSCs, mtDNA damage was no longer detected in differentiated neuroprogenitor and neural cells. Our results unambiguously link LRRK2 mutations to mtDNA damage and validate a new cellular phenotype that can be used for examining pathogenic mechanisms and screening therapeutic strategies. •LRRK2 PD-associated mutations induce mtDNA damage in iPSC-derived neural cells•MtDNA damage is functionally reversed by ZFN-mediated genome editing•MtDNA damage is an early biomarker of LRRK2-related PD neuronal dysfunction