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Published on: June 23, 2023
Mitochondrial DNA heteroplasmy distinguishes disease manifestation in PINK1/PRKN-linked Parkinson's disease
Joanne Trinh1, Andrew A Hicks2, Inke R König3
1Institute of Neurogenetics, University of Lübeck, Lübeck 23562, Germany.
Abstract:
Biallelic mutations in PINK1/PRKN cause recessive Parkinson's disease. Given the established role of PINK1/Parkin in regulating mitochondrial dynamics, we explored mitochondrial DNA integrity and inflammation as disease modifiers in carriers of mutations in these genes. Mitochondrial DNA integrity was investigated in a large collection of biallelic (n = 84) and monoallelic (n = 170) carriers of PINK1/PRKN mutations, idiopathic Parkinson's disease patients (n = 67) and controls (n = 90). In addition, we studied global gene expression and serum cytokine levels in a subset. Affected and unaffected PINK1/PRKN monoallelic mutation carriers can be distinguished by heteroplasmic mitochondrial DNA variant load (area under the curve = 0.83, CI 0.74-0.93). Biallelic PINK1/PRKN mutation carriers harbour more heteroplasmic mitochondrial DNA variants in blood (P = 0.0006, Z = 3.63) compared to monoallelic mutation carriers. This enrichment was confirmed in induced pluripotent stem cell-derived (controls, n = 3; biallelic PRKN mutation carriers, n = 4) and post-mortem (control, n = 1; biallelic PRKN mutation carrier, n = 1) midbrain neurons. Last, the heteroplasmic mitochondrial DNA variant load correlated with IL6 levels in PINK1/PRKN mutation carriers (r = 0.57, P = 0.0074). PINK1/PRKN mutations predispose individuals to mitochondrial DNA variant accumulation in a dose- and disease-dependent manner.
Insights
Mutations in PINK1/Parkin (PRKN) genes impact mitochondrial DNA integrity. Increased mitochondrial DNA variants correlate with disease severity and inflammation (IL6) in Parkinson's disease patients.
Area of Science:
- Neurogenetics
- Mitochondrial Biology
- Inflammation Research
Background:
- Biallelic mutations in PTEN-induced kinase 1 (PINK1) and Parkin (PRKN) are established causes of recessive Parkinson's disease.
- PINK1 and Parkin play critical roles in mitochondrial dynamics and quality control.
- Mitochondrial dysfunction and neuroinflammation are increasingly recognized as key contributors to Parkinson's pathogenesis.
Purpose of the Study:
- To investigate mitochondrial DNA (mtDNA) integrity and inflammation as potential disease modifiers in carriers of PINK1/PRKN mutations.
- To determine if mtDNA integrity differs between biallelic and monoallelic PINK1/PRKN mutation carriers.
- To explore the relationship between mtDNA variant load, gene expression, and serum cytokine levels.
Main Methods:
- Analysis of mtDNA integrity using heteroplasmic variant load in a large cohort of biallelic (n=84) and monoallelic (n=170) PINK1/PRKN mutation carriers, idiopathic Parkinson's disease patients (n=67), and controls (n=90).
- Global gene expression profiling and serum cytokine measurements in a subset of participants.
- Validation of mtDNA variant enrichment in induced pluripotent stem cell-derived and post-mortem midbrain neurons.
Main Results:
- Heteroplasmic mtDNA variant load effectively distinguished affected and unaffected monoallelic PINK1/PRKN mutation carriers (AUC=0.83).
- Biallelic PINK1/PRKN mutation carriers exhibited significantly higher heteroplasmic mtDNA variant loads in blood compared to monoallelic carriers (P=0.0006).
- mtDNA variant enrichment was confirmed in neuronal cells and correlated significantly with Interleukin-6 (IL6) levels in mutation carriers (r=0.57, P=0.0074).
Conclusions:
- PINK1/PRKN mutations are associated with an accumulation of mtDNA variants in a dose- and disease-dependent manner.
- mtDNA integrity serves as a potential biomarker to differentiate disease states in PINK1/PRKN mutation carriers.
- Mitochondrial DNA variant load is linked to inflammatory markers, suggesting a role for mtDNA integrity in modulating Parkinson's disease progression.
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