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Published on: December 14, 2017
Mitochondrial Mechanisms of LRRK2 G2019S Penetrance
Sylvie Delcambre1, Jenny Ghelfi1, Nassima Ouzren1
1Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
Abstract:
Several mutations in leucine-rich repeat kinase-2 (LRRK2) have been associated with Parkinson's disease (PD). The most common substitution, G2019S, interferes with LRRK2 kinase activity, which is regulated by autophosphorylation. Yet, the penetrance of this gain-of-function mutation is incomplete, and thus far, few factors have been correlated with disease status in carriers. This includes (i) LRRK2 autophosphorylation in urinary exosomes, (ii) serum levels of the antioxidant urate, and (iii) abundance of mitochondrial DNA (mtDNA) transcription-associated 7S DNA. In light of a mechanistic link between LRRK2 kinase activity and mtDNA lesion formation, we previously investigated mtDNA integrity in fibroblasts from manifesting (LRRK2+/PD+) and non-manifesting carriers (LRRK2+/PD-) of the G2019S mutation as well as from aged-matched controls. In our published study, mtDNA major arc deletions correlated with PD status, with manifesting carriers presenting the highest levels. In keeping with these findings, we now further explored mitochondrial features in fibroblasts derived from LRRK2+/PD+ (n = 10), LRRK2+/PD- (n = 21), and control (n = 10) individuals. In agreement with an accumulation of mtDNA major arc deletions, we also detected reduced NADH dehydrogenase activity in the LRRK2+/PD+ group. Moreover, in affected G2019S carriers, we observed elevated mitochondrial mass and mtDNA copy numbers as well as increased expression of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates antioxidant signaling. Taken together, these results implicate mtDNA dyshomeostasis-possibly as a consequence of impaired mitophagy-in the penetrance of LRRK2-associated PD. Our findings are a step forward in the pursuit of unveiling markers that will allow monitoring of disease progression of LRRK2 mutation carriers.
Insights
Mutations in leucine-rich repeat kinase-2 (LRRK2) are linked to Parkinson's disease (PD). This study found mitochondrial DNA (mtDNA) damage and dysfunction in G2019S carriers with PD, suggesting a role in disease penetrance.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Mutations in leucine-rich repeat kinase-2 (LRRK2) are a significant genetic factor in Parkinson's disease (PD).
- The G2019S mutation, a common gain-of-function variant, affects LRRK2 kinase activity but has incomplete penetrance.
- Factors influencing PD status in LRRK2 mutation carriers are not fully understood, prompting investigation into cellular mechanisms.
Purpose of the Study:
- To investigate mitochondrial features in fibroblasts from individuals with the LRRK2 G2019S mutation, comparing manifesting PD patients, non-manifesting carriers, and controls.
- To explore the relationship between LRRK2 kinase activity, mitochondrial DNA (mtDNA) integrity, and PD status.
- To identify potential biomarkers for monitoring disease progression in LRRK2 mutation carriers.
Main Methods:
- Fibroblast cultures were established from individuals with LRRK2+/PD+ (n=10), LRRK2+/PD- (n=21), and age-matched controls (n=10).
- Analysis included assessment of mtDNA major arc deletions, NADH dehydrogenase activity, mitochondrial mass, mtDNA copy numbers, and nuclear factor erythroid 2-related factor 2 (Nrf2) expression.
- Previous findings on mtDNA integrity were corroborated and expanded with further mitochondrial analyses.
Main Results:
- LRRK2+/PD+ individuals exhibited significantly higher levels of mtDNA major arc deletions compared to non-manifesting carriers and controls.
- Reduced NADH dehydrogenase activity was observed in the LRRK2+/PD+ group, consistent with mtDNA damage.
- Elevated mitochondrial mass, increased mtDNA copy numbers, and higher Nrf2 expression were detected in affected G2019S carriers.
Conclusions:
- Mitochondrial DNA (mtDNA) dyshomeostasis, potentially due to impaired mitophagy, is implicated in the incomplete penetrance of LRRK2-associated Parkinson's disease.
- These findings highlight the role of mitochondrial dysfunction in LRRK2 PD pathogenesis.
- The study provides insights into potential biomarkers for tracking disease progression in LRRK2 mutation carriers.
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