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LRRK2 G2019S-induced mitochondrial DNA damage is LRRK2 kinase dependent and inhibition restores mtDNA integrity in Parkinson's disease.
Hum Mol Genet 2017; 26(22):4340-4351HM

Abstract

Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with increased risk for developing Parkinson's disease (PD). Previously, we found that LRRK2 G2019S mutation carriers have increased mitochondrial DNA (mtDNA) damage and after zinc finger nuclease-mediated gene mutation correction, mtDNA damage was no longer detectable. While the mtDNA damage phenotype can be unambiguously attributed to the LRRK2 G2019S mutation, the underlying mechanism(s) is unknown. Here, we examine the role of LRRK2 kinase function in LRRK2 G2019S-mediated mtDNA damage, using both genetic and pharmacological approaches in cultured neurons and PD patient-derived cells. Expression of LRRK2 G2019S induced mtDNA damage in primary rat midbrain neurons, but not in cortical neuronal cultures. In contrast, the expression of LRRK2 wild type or LRRK2 D1994A mutant (kinase dead) had no effect on mtDNA damage in either midbrain or cortical neuronal cultures. In addition, human LRRK2 G2019S patient-derived lymphoblastoid cell lines (LCL) demonstrated increased mtDNA damage relative to age-matched controls. Importantly, treatment of LRRK2 G2019S expressing midbrain neurons or patient-derived LRRK2 G2019S LCLs with the LRRK2 kinase inhibitor GNE-7915, either prevented or restored mtDNA damage to control levels. These findings support the hypothesis that LRRK2 G2019S-induced mtDNA damage is LRRK2 kinase activity dependent, uncovering a novel pathological role for this kinase. Blocking or reversing mtDNA damage via LRRK2 kinase inhibition or other therapeutic approaches may be useful to slow PD-associated pathology.

Authors+Show Affiliations

Department of Neurology, Pittsburgh Institute for Neurodegenerative Diseases.Department of Neurology, Pittsburgh Institute for Neurodegenerative Diseases.Department of Medicine, Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA.Parkinson's Institute and Clinical Center, Sunnyvale, CA 94085, USA.Department of Neurology, Pittsburgh Institute for Neurodegenerative Diseases.Department of Neurology, Pittsburgh Institute for Neurodegenerative Diseases.Parkinson's Institute and Clinical Center, Sunnyvale, CA 94085, USA.Department of Medicine, Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA.Department of Neurology, Pittsburgh Institute for Neurodegenerative Diseases.Department of Neurology, Duke University Medical Center, Durham, NC 27710, USA.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

28973664

Citation

Howlett, Evan H., et al. "LRRK2 G2019S-induced Mitochondrial DNA Damage Is LRRK2 Kinase Dependent and Inhibition Restores mtDNA Integrity in Parkinson's Disease." Human Molecular Genetics, vol. 26, no. 22, 2017, pp. 4340-4351.
Howlett EH, Jensen N, Belmonte F, et al. LRRK2 G2019S-induced mitochondrial DNA damage is LRRK2 kinase dependent and inhibition restores mtDNA integrity in Parkinson's disease. Hum Mol Genet. 2017;26(22):4340-4351.
Howlett, E. H., Jensen, N., Belmonte, F., Zafar, F., Hu, X., Kluss, J., ... Sanders, L. H. (2017). LRRK2 G2019S-induced mitochondrial DNA damage is LRRK2 kinase dependent and inhibition restores mtDNA integrity in Parkinson's disease. Human Molecular Genetics, 26(22), pp. 4340-4351. doi:10.1093/hmg/ddx320.
Howlett EH, et al. LRRK2 G2019S-induced Mitochondrial DNA Damage Is LRRK2 Kinase Dependent and Inhibition Restores mtDNA Integrity in Parkinson's Disease. Hum Mol Genet. 2017 11 15;26(22):4340-4351. PubMed PMID: 28973664.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - LRRK2 G2019S-induced mitochondrial DNA damage is LRRK2 kinase dependent and inhibition restores mtDNA integrity in Parkinson's disease. AU - Howlett,Evan H, AU - Jensen,Nicholas, AU - Belmonte,Frances, AU - Zafar,Faria, AU - Hu,Xiaoping, AU - Kluss,Jillian, AU - Schüle,Birgitt, AU - Kaufman,Brett A, AU - Greenamyre,J T, AU - Sanders,Laurie H, PY - 2017/05/30/received PY - 2017/08/10/accepted PY - 2017/10/4/pubmed PY - 2018/3/22/medline PY - 2017/10/4/entrez SP - 4340 EP - 4351 JF - Human molecular genetics JO - Hum. Mol. Genet. VL - 26 IS - 22 N2 - Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with increased risk for developing Parkinson's disease (PD). Previously, we found that LRRK2 G2019S mutation carriers have increased mitochondrial DNA (mtDNA) damage and after zinc finger nuclease-mediated gene mutation correction, mtDNA damage was no longer detectable. While the mtDNA damage phenotype can be unambiguously attributed to the LRRK2 G2019S mutation, the underlying mechanism(s) is unknown. Here, we examine the role of LRRK2 kinase function in LRRK2 G2019S-mediated mtDNA damage, using both genetic and pharmacological approaches in cultured neurons and PD patient-derived cells. Expression of LRRK2 G2019S induced mtDNA damage in primary rat midbrain neurons, but not in cortical neuronal cultures. In contrast, the expression of LRRK2 wild type or LRRK2 D1994A mutant (kinase dead) had no effect on mtDNA damage in either midbrain or cortical neuronal cultures. In addition, human LRRK2 G2019S patient-derived lymphoblastoid cell lines (LCL) demonstrated increased mtDNA damage relative to age-matched controls. Importantly, treatment of LRRK2 G2019S expressing midbrain neurons or patient-derived LRRK2 G2019S LCLs with the LRRK2 kinase inhibitor GNE-7915, either prevented or restored mtDNA damage to control levels. These findings support the hypothesis that LRRK2 G2019S-induced mtDNA damage is LRRK2 kinase activity dependent, uncovering a novel pathological role for this kinase. Blocking or reversing mtDNA damage via LRRK2 kinase inhibition or other therapeutic approaches may be useful to slow PD-associated pathology. SN - 1460-2083 UR - https://www.unboundmedicine.com/medline/citation/28973664/LRRK2_G2019S_induced_mitochondrial_DNA_damage_is_LRRK2_kinase_dependent_and_inhibition_restores_mtDNA_integrity_in_Parkinson's_disease_ L2 - https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddx320 DB - PRIME DP - Unbound Medicine ER -