LRRK2 mutations cause mitochondrial DNA damage in iPSC-derived neural cells from Parkinson's disease patients: Reversal by gene correction
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 mit...
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doaj-d505d3408a924944819f08f5874cf1682021-03-22T12:40:33ZengElsevierNeurobiology of Disease1095-953X2014-02-0162381386LRRK2 mutations cause mitochondrial DNA damage in iPSC-derived neural cells from Parkinson's disease patients: Reversal by gene correctionLaurie H. Sanders0Josée Laganière1Oliver Cooper2Sally K. Mak3B. Joseph Vu4Y. Anne Huang5David E. Paschon6Malini Vangipuram7Ramya Sundararajan8Fyodor D. Urnov9J. William Langston10Philip D. Gregory11H. Steve Zhang12J. Timothy Greenamyre13Ole Isacson14Birgitt Schüle15Pittsburgh Institute for Neurodegenerative Diseases, Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15260, USASangamo BioSciences, Inc., Point Richmond Tech Center, 501 Canal Boulevard, Suite A100, Richmond, CA 94804, USANeuroregeneration Institute, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USAThe Parkinson's Institute, 675 Almanor Avenue, Sunnyvale, CA 94025, USASangamo BioSciences, Inc., Point Richmond Tech Center, 501 Canal Boulevard, Suite A100, Richmond, CA 94804, USAThe Parkinson's Institute, 675 Almanor Avenue, Sunnyvale, CA 94025, USASangamo BioSciences, Inc., Point Richmond Tech Center, 501 Canal Boulevard, Suite A100, Richmond, CA 94804, USAThe Parkinson's Institute, 675 Almanor Avenue, Sunnyvale, CA 94025, USAThe Parkinson's Institute, 675 Almanor Avenue, Sunnyvale, CA 94025, USASangamo BioSciences, Inc., Point Richmond Tech Center, 501 Canal Boulevard, Suite A100, Richmond, CA 94804, USAThe Parkinson's Institute, 675 Almanor Avenue, Sunnyvale, CA 94025, USASangamo BioSciences, Inc., Point Richmond Tech Center, 501 Canal Boulevard, Suite A100, Richmond, CA 94804, USASangamo BioSciences, Inc., Point Richmond Tech Center, 501 Canal Boulevard, Suite A100, Richmond, CA 94804, USAPittsburgh Institute for Neurodegenerative Diseases, Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15260, USA; Correspondence to: J.T. Greenamyre, University of Pittsburgh, 3501 Fifth Avenue, Suite 7039, Pittsburgh, PA 15260, USA. Fax: +1 412 648 9766.Neuroregeneration Institute, McLean Hospital/Harvard Medical School, Belmont, MA 02478, USA; Correspondence to: O. Isacson, Neuroregeneration Institute, McLean Hospital/Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA. Fax: +1 617 855 2522.The Parkinson's Institute, 675 Almanor Avenue, Sunnyvale, CA 94025, USA; Correspondence to: B. Schüle, Parkinson's Institute, 675 Almanor Avenue, Sunnyvale, CA 94085, USA. Fax: +1 408 734 8455.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.http://www.sciencedirect.com/science/article/pii/S096999611300288XParkinson's diseaseLRRK2Mitochondrial DNA damageStem cells |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Laurie H. Sanders Josée Laganière Oliver Cooper Sally K. Mak B. Joseph Vu Y. Anne Huang David E. Paschon Malini Vangipuram Ramya Sundararajan Fyodor D. Urnov J. William Langston Philip D. Gregory H. Steve Zhang J. Timothy Greenamyre Ole Isacson Birgitt Schüle |
spellingShingle |
Laurie H. Sanders Josée Laganière Oliver Cooper Sally K. Mak B. Joseph Vu Y. Anne Huang David E. Paschon Malini Vangipuram Ramya Sundararajan Fyodor D. Urnov J. William Langston Philip D. Gregory H. Steve Zhang J. Timothy Greenamyre Ole Isacson Birgitt Schüle LRRK2 mutations cause mitochondrial DNA damage in iPSC-derived neural cells from Parkinson's disease patients: Reversal by gene correction Neurobiology of Disease Parkinson's disease LRRK2 Mitochondrial DNA damage Stem cells |
author_facet |
Laurie H. Sanders Josée Laganière Oliver Cooper Sally K. Mak B. Joseph Vu Y. Anne Huang David E. Paschon Malini Vangipuram Ramya Sundararajan Fyodor D. Urnov J. William Langston Philip D. Gregory H. Steve Zhang J. Timothy Greenamyre Ole Isacson Birgitt Schüle |
author_sort |
Laurie H. Sanders |
title |
LRRK2 mutations cause mitochondrial DNA damage in iPSC-derived neural cells from Parkinson's disease patients: Reversal by gene correction |
title_short |
LRRK2 mutations cause mitochondrial DNA damage in iPSC-derived neural cells from Parkinson's disease patients: Reversal by gene correction |
title_full |
LRRK2 mutations cause mitochondrial DNA damage in iPSC-derived neural cells from Parkinson's disease patients: Reversal by gene correction |
title_fullStr |
LRRK2 mutations cause mitochondrial DNA damage in iPSC-derived neural cells from Parkinson's disease patients: Reversal by gene correction |
title_full_unstemmed |
LRRK2 mutations cause mitochondrial DNA damage in iPSC-derived neural cells from Parkinson's disease patients: Reversal by gene correction |
title_sort |
lrrk2 mutations cause mitochondrial dna damage in ipsc-derived neural cells from parkinson's disease patients: reversal by gene correction |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2014-02-01 |
description |
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. |
topic |
Parkinson's disease LRRK2 Mitochondrial DNA damage Stem cells |
url |
http://www.sciencedirect.com/science/article/pii/S096999611300288X |
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