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

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 DNA DX ) 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 DNA DX assay may have utility as a candidate marker of PD and for measuring the pharmacodynamic response to LRRK2 kinase inhibitors.

Perspectives of People At-Risk on Parkinson’s Prevention Research

“…Moreover, lower penetrance rates in genetically at-risk individuals such as carriers of pathogenic LRRK2 or GBA variants complicate trial design and statistical power in the absence of established validated biomarkers for these targets that go beyond alpha synuclein. However, low-risk prevention interventions in genetically at-risk individuals remain promising because the underlying biological and pathological mechanisms are more elucidated [ 49 ], biomarker research is progressing quickly [ 50, 51 ], and at-risk individuals can be identified very early [ 52 ]. In addition, direct-to-consumer genetic testing companies such as 23andMe as well as research initiatives such as PPMI and the Rostock International Parkinson’s Disease Study (ROPAD) have already identified over 4,000 contactable, non-manifesting carriers of the LRRK2 G2019 S variant and even more with pathologic GBA variants [ 53 ].…”

Longitudinal immunophenotyping to track motor progression in Parkinson’s Associated with a TH mutation

“…Currently, tracking the progression of PD or its response to symptomatic treatments, such as levodopa, has been attempted using imaging modalities such as DAT and MRI, as well as skin biopsy and MIBG cardiac testing 8–13,14 . While recent research has highlighted several promising disease progression markers 15–17 , their longitudinal applicability in monitoring progression for individual PD patients has not been clearly demonstrated.…”

Advancing precision medicine therapeutics for Parkinson’s utilizing a shared quantitative systems pharmacology model and framework

“…Moreover, in a review of about 121 trials in neurodegenerative diseases, less than half reported the use of central biomarkers, and a little more than half of trials included at least one target occupancy/ activation biomarker . However, there is reason for optimism in this area given the rapid progress being made in the development of biomarkers as drug development tools for Neurodegenerative diseases (Marks et al, 2021;Qi et al, 2023) and in PD specifically. Recent progress in biomarkers for PD has advanced with the identification of disease hallmark signatures that were previously only detected at autopsy to confirm pathologic diagnosis.…”