A blood-based marker of mitochondrial DNA damage in Parkinson's disease

TY - JOUR

T1 - A blood-based marker of mitochondrial DNA damage in Parkinson's disease

AU - Qi, Rui

AU - Sammler, Esther

AU - Gonzalez-Hunt, Claudia P.

AU - Barraza, Ivana

AU - Pena, Nicholas

AU - Rouanet, Jeremy P.

AU - Naaldijk, Yahaira

AU - Goodson, Steven

AU - Fuzzati, Marie

AU - Blandini, Fabio

AU - Erickson, Kirk I.

AU - Weinstein, Andrea M.

AU - Lutz, Michael W.

AU - Kwok, John B.

AU - Halliday, Glenda M.

AU - Dzamko, Nicolas

AU - Padmanabhan, Shalini

AU - Alcalay, Roy N.

AU - Waters, Cheryl

AU - Hogarth, Penelope

AU - Simuni, Tanya

AU - Smith, Danielle

AU - Marras, Connie

AU - Tonelli, Francesca

AU - Alessi, Dario R.

AU - West, Andrew B.

AU - Shiva, Sruti

AU - Hilfiker, Sabine

AU - Sanders, Laurie H.

N1 - Copyright: © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

PY - 2023/8/30

Y1 - 2023/8/30

N2 - Parkinson's disease (PD) is the most common neurodegenerative movement disorder, and neuroprotective or disease-modifying interventions remain elusive. High-throughput markers aimed at stratifying patients on the basis of shared etiology are required to ensure the success of disease-modifying therapies in clinical trials. Mitochondrial dysfunction plays a prominent role in the pathogenesis of PD. Previously, we found brain region-specific accumulation of mitochondrial DNA (mtDNA) damage in PD neuronal culture and animal models, as well as in human PD postmortem brain tissue. To investigate mtDNA damage as a potential blood-based marker for PD, we describe herein a PCR-based assay (Mito DNADX) that allows for the accurate real-time quantification of mtDNA damage in a scalable platform. We found that mtDNA damage was increased in peripheral blood mononuclear cells derived from patients with idiopathic PD and those harboring the PD-associated leucine-rich repeat kinase 2 (LRRK2) G2019S mutation in comparison with age-matched controls. In addition, mtDNA damage was elevated in non-disease-manifesting LRRK2 mutation carriers, demonstrating that mtDNA damage can occur irrespective of a PD diagnosis. We further established that Lrrk2 G2019S knock-in mice displayed increased mtDNA damage, whereas Lrrk2 knockout mice showed fewer mtDNA lesions in the ventral midbrain, compared with wild-type control mice. Furthermore, a small-molecule kinase inhibitor of LRRK2 mitigated mtDNA damage in a rotenone PD rat midbrain neuron model and in idiopathic PD patient-derived lymphoblastoid cell lines. Quantifying mtDNA damage using the Mito DNADX assay may have utility as a candidate marker of PD and for measuring the pharmacodynamic response to LRRK2 kinase inhibitors.

AB - Parkinson's disease (PD) is the most common neurodegenerative movement disorder, and neuroprotective or disease-modifying interventions remain elusive. High-throughput markers aimed at stratifying patients on the basis of shared etiology are required to ensure the success of disease-modifying therapies in clinical trials. Mitochondrial dysfunction plays a prominent role in the pathogenesis of PD. Previously, we found brain region-specific accumulation of mitochondrial DNA (mtDNA) damage in PD neuronal culture and animal models, as well as in human PD postmortem brain tissue. To investigate mtDNA damage as a potential blood-based marker for PD, we describe herein a PCR-based assay (Mito DNADX) that allows for the accurate real-time quantification of mtDNA damage in a scalable platform. We found that mtDNA damage was increased in peripheral blood mononuclear cells derived from patients with idiopathic PD and those harboring the PD-associated leucine-rich repeat kinase 2 (LRRK2) G2019S mutation in comparison with age-matched controls. In addition, mtDNA damage was elevated in non-disease-manifesting LRRK2 mutation carriers, demonstrating that mtDNA damage can occur irrespective of a PD diagnosis. We further established that Lrrk2 G2019S knock-in mice displayed increased mtDNA damage, whereas Lrrk2 knockout mice showed fewer mtDNA lesions in the ventral midbrain, compared with wild-type control mice. Furthermore, a small-molecule kinase inhibitor of LRRK2 mitigated mtDNA damage in a rotenone PD rat midbrain neuron model and in idiopathic PD patient-derived lymphoblastoid cell lines. Quantifying mtDNA damage using the Mito DNADX assay may have utility as a candidate marker of PD and for measuring the pharmacodynamic response to LRRK2 kinase inhibitors.

U2 - 10.1126/scitranslmed.abo1557

DO - 10.1126/scitranslmed.abo1557

M3 - Article

C2 - 37647388

AN - SCOPUS:85169230262

SN - 1946-6234

VL - 15

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 711

M1 - eabo1557

ER -