Mitochondrial damage-associated inflammation highlights biomarkers in PRKN/PINK1 parkinsonism

Abstract

There is increasing evidence for a role of inflammation in Parkinson’s disease. Recent research in murine models suggests that parkin and PINK1 deficiency leads to impaired mitophagy, which causes the release of mitochondrial DNA (mtDNA), thereby triggering inflammation. Specifically, the CGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) pathway mitigates activation of the innate immune system, quantifiable as increased interleukin-6 (IL6) levels. However, the role of IL6 and circulating cell-free mtDNA in unaffected and affected individuals harbouring mutations in PRKN/PINK1 and idiopathic Parkinson’s disease patients remain elusive. We investigated IL6, C-reactive protein, and circulating cell-free mtDNA in serum of 245 participants in two cohorts from tertiary movement disorder centres. We performed a hypothesis-driven rank-based statistical approach adjusting for multiple testing. We detected (i) elevated IL6 levels in patients with biallelic PRKN/PINK1 mutations compared to healthy control subjects in a German cohort, supporting the concept of a role for inflammation in PRKN/PINK1-linked Parkinson’s disease. In addition, the comparison of patients with biallelic and heterozygous mutations in PRKN/PINK1 suggests a gene dosage effect. The differences in IL6 levels were validated in a second independent Italian cohort; (ii) a correlation between IL6 levels and disease duration in carriers of PRKN/PINK1 mutations, while no such association was observed for idiopathic Parkinson’s disease patients. These results highlight the potential of IL6 as progression marker in Parkinson’s disease due to PRKN/PINK1 mutations; (iii) increased circulating cell-free mtDNA serum levels in both patients with biallelic or with heterozygous PRKN/PINK1 mutations compared to idiopathic Parkinson’s disease, which is in line with previous findings in murine models. By contrast, circulating cell-free mtDNA concentrations in unaffected heterozygous carriers of PRKN/PINK1 mutations were comparable to control levels; and (iv) that circulating cell-free mtDNA levels have good predictive potential to discriminate between idiopathic Parkinson’s disease and Parkinson’s disease linked to heterozygous PRKN/PINK1 mutations, providing functional evidence for a role of heterozygous mutations in PRKN or PINK1 as Parkinson’s disease risk factor. Taken together, our study further implicates inflammation due to impaired mitophagy and subsequent mtDNA release in the pathogenesis of PRKN/PINK1-linked Parkinson’s disease. In individuals carrying mutations in PRKN/PINK1, IL6 and circulating cell-free mtDNA levels may serve as markers of Parkinson’s disease state and progression, respectively. Finally, our study suggests that targeting the immune system with anti-inflammatory medication holds the potential to influence the disease course of Parkinson’s disease, at least in this subset of patients.

Targeting mitophagy in Parkinson's disease

“… Blood (cell fractions)—qPCR Stratification, efficacy ( 201 , 202 , 203 ) ccf-mtDNA Reduced in PD CSF but increased in serum of PINK1 and Parkin PD patients. CSF—qPCR Stratification, efficacy (may require treatment-naive patients) ( 204 , 241 , 242 ) Inflammation IL-6 Elevated in serum of sporadic PD patients, Parkin PD patients, and Parkin heterozygotes. Some studies have found correlations between IL-6 levels and PD severity.…”

“…Some studies have found correlations between IL-6 levels and PD severity. Serum—ELISA, cytokine immunoassays Stratification, efficacy ( 156 , 204 , 206 , 207 , 208 ) Imaging Magnetic resonance spectroscopy (MRS) Hydrogen nucleus ( 1 H) MRS: N-acetylaspartate is reduced in PD patient brain and can be improved by dopamine replacement therapies. Lactate is elevated in PD patient brain.…”

Crosstalk between Different DNA Repair Pathways Contributes to Neurodegenerative Diseases

“…In iPSC derived ALS patient motor neurons, TDP-43 triggered the release of mtDNA, leading to cGAS-STING activation, and neuroinflammation has been shown [ 181 ]. The induction of IL6 in response to circulating cell-free mtDNA has been reported in Parkinson patients’ serum [ 182 ]. Hence, cGAS-STING mediated inflammation emerges as another common characteristic of NDDs.…”

“Empowering” Cardiac Cells via Stem Cell Derived Mitochondrial Transplantation- Does Age Matter?

“…These molecules, also called mitochondrial Damage-Associated Molecular Patterns (DAMPs), which are typically released during the course of cell death, mediate inflammatory immune responses and are associated with pathogenicity and severity of various diseases. Mitochondrial DNA/DAMPs have been found in brain death, trauma patients, sepsis, neurologic (ischemic stroke and bacterial meningitis) and myocardial injury and were associated with early allograft dysfunction and acute respiratory distress syndrome (ARDS) [ 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 ]. McCully et al compared the transplantation of whole mitochondria, mitochondrial components and frozen-thawed mitochondria [ 4 ].…”