Abstract
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.
| Original language | English (US) |
|---|---|
| Article number | eabo1557 |
| Journal | Science translational medicine |
| Volume | 15 |
| Issue number | 711 |
| DOIs | |
| State | Published - Aug 2023 |
Funding
Funding: This work was supported, in part, by grants fromthe MJFF for Parkinson’s research (to D.R.A.andL.H.S.);theMitochondria,AgingandMetabolismSeedGrantProgram(toS.S.and L.H.S.);theWilliamN.andBerniceE.BumpusFoundation(toL.H.S.);NIHF31NS089111and 1K23AG076663(toA.M.W .); PepperCenterattheUniversityofPittsburghP30AG024827(to K.I.E.,A.M.W ., andL.H.S.);MedicalResearchCouncilUKRIgrantMCUU12016/2(toD.R.A.);Chief ScientistOfficeSeniorClinicalAcademicFellowshipSCAF/18/01(toE.S.);theNationalHealth andMedicalResearchCouncilofAustraliaLeadershipFellowship(toG.M.H.);BuschBiomedical Researchgrant(toS.H.);NIHR01NS064934(toA.B.W .); andNIHP50AG005133and RO1NS119528(toL.H.S.).Authorcontributions:R.Q.,C.P .G-H., I.B.,N.P ., S.G.,S.H.,andL.H.S. designed,performed,andanalyzedMitoDNADXstudies.E.S.,F .T ., andD.R.A.performedand analyzedLRRK2biomarkerstudies.J.P .R., R.N.A.,C.W ., P .H., T .S., D.S.,C.M.,M.F ., F .B., J.B.K.,G.M.H., andN.D.providedhumancelllinesorrecruitedparticipants.Y .N. andS.H.performedasubsetof theLCLexperiments.M.W .L. performedorprovidedguidanceforstatisticalanalysis.A.B.W . providedandanalyzedLrrk2K Omousestudies.S.S.providedresourcesandsupervisionforthe studies. L.H.S. conceptualized and designed experiments and provided resources and supervisionforthestudies.R.Q.,E.S.,andL.H.S.wrotethemanuscriptwithinputfromall authors. All authors contributed to reviewing the final version of the manuscript. Competing interests:L.H.S.andS.S.arecoinventorsonUSpatentapplicationnumber17/227,186entitled “Mitochondrial health parameters as clinical predictors of Parkinson’s disease. ” L.H.S. is on the scientific advisory board of Lucy Therapeutics. R.N.A. received consultation fees from A vr obio, Biohaven,Capsida,Caraway,GainTherapeutics,Genzyme/Sanofi,andTakeda.C.M.actedas advisor to the MJFF for the creation and management of FBN. C.M. received funding from the MJFFastheprincipalinvestiga tor ofFBN.T .S. hasservedasaconsultantforAcureX,Adamas, AskBio, Amneal, Blue Rock Therapeutics, Critical Pa th for Parkinson’s Consortium (CPP), Denali, MJFF ,Neuroderm,Sanofi,Sinopia,Roche,Takeda,andVanquaBio.T .S. servedontheadboard forAcureX,Adamas,AskBio,Denali,andRoche.T .S. hasservedasamemberofthescientific advisoryboardofNeuroderm,Sanofi,andUCB.T .S. hasreceivedresearchfundingfromAmneal, Biogen,Neuroderm,Prevail,Roche,andUCBandisaninvestigatorforNationalInstituteof Neurological Disorders and Strok e (NINDS), MJFF , and the Parkinson’s Foundation. The other authorsdeclarethattheyhav enocompetinginterests.Dataandmaterialsavailability:All dataassociatedwiththisstudyarepresentinthepaperortheSupplementaryMaterials.Raw dataareavailableindatafileS1.TheLCLsobtainedfromtheNINDSCoriellbiorepositoryare freelyaccessibletotheresearchcommunity(https://coriell.org/1/NINDS). This work was supported, in part, by grants from the MJFF for Parkinson's research (to D.R.A. and L.H.S.); the Mitochondria, Aging and Metabolism Seed Grant Program (to S.S. and L.H.S.); the William N. and Bernice E. Bumpus Foundation (to L.H.S.); NIH F31NS089111 and 1K23AG076663 (to A.M.W.); Pepper Center at the University of Pittsburgh P30AG024827 (to K.I.E., A.M.W., and L.H.S.); Medical Research Council UKRI grant MCUU12016/2 (to D.R.A.); Chief Scientist Office Senior Clinical Academic Fellowship SCAF/18/01 (to E.S.); the National Health and Medical Research Council of Australia Leadership Fellowship (to G.M.H.); Busch Biomedical Research grant (to S.H.); NIH R01NS064934 (to A.B.W.); and NIH P50AG005133 and RO1NS119528 (to L.H.S.).
ASJC Scopus subject areas
- General Medicine
