Parkinson's disease (PD) is a common neurodegenerative movement disorder and leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for disease intervention. However, the ability to stratify patients who will benefit from such treatment modalities based on shared etiology is critical for the success of disease-modifying therapies. Ciliary and centrosomal alterations are commonly associated with pathogenic LRRK2 kinase activity and can be detected in many cell types. We previously found centrosomal deficits in immortalized lymphocytes from G2019S-LRRK2 PD patients. Here, to investigate whether such deficits may serve as a potential blood biomarker for PD which is susceptible to LRKK2 inhibitor treatment, we characterized patient-derived cells from distinct PD cohorts. We report centrosomal alterations in peripheral cells from a subset of early-stage idiopathic PD patients which is mitigated by LRRK2 kinase inhibition, supporting a role for aberrant LRRK2 activity in idiopathic PD. Centrosomal defects are detected in R1441G-LRRK2 and G2019S-LRRK2 PD patients and in non-manifesting LRRK2 mutation carriers, indicating that they acumulate prior to a clinical PD diagnosis. They are present in immortalized cells as well as in primary lymphocytes from peripheral blood. These findings indicate that analysis of centrosomal defects as a blood-based patient stratification biomarker may help nominate PD patients who will benefit from LRRK2-related therapeutics.
People who inject drugs (PWID) are a population exposed to many genotoxicants and with a high prevalence of HCV infection. Direct-acting antiviral (DAA) regimens are now widely used to treat chronic HCV infection. Although side effects to treatment are currently rare, the long-term effects such as suspicions of de novo hepatocellular carcinoma (HCC) occurrence or HCC recurrence and cardiac defects are still up for debate. Given the structure of DAAs, the molecules have a potential mitochondrial DNA (mtDNA) genotoxicity. We have previously reported acute mtDNA toxicity of three DAA regimens among PWID with a strong impact on the rate of mtDNA deletion, less on the quantity of mtDNA copy per cell at sustained viral response at 12 weeks (SVR12). Herein, we report the mtDNA parameters nine months after drug discontinuation. We observed that the percentage of the deleted mtDNA genome increased over time. No exposure to any other genotoxicants during this period was associated with a high deletion percentage, suggesting that the replicative advantage of the deleted molecules outweighed their elimination processes. Such observation calls for longer-term follow-up and may contribute to the molecular basis of subclinical side effects of DAA treatments.
HIV-exposed uninfected (HEU) children show impaired health outcomes during childhood. A high rate of mitochondrial DNA (mtDNA) instability was reported in the blood of HEU at birth. We aimed to explore the relationship between these health outcomes and mtDNA deletions over time in a case series of 24 HEU children. MtDNA instability was assessed by deep sequencing and analyzed by eKLIPse-v2 algorithm at three time points, namely birth, 1 year, and 6 years of age. Association between mtDNA deletion and health outcomes, including growth, clinical, and neurodevelopmental parameters, were explored using univariate statistical analyses and after stratification with relevant variables. HEU children were selected with an equal male:female ratio. An elevated number of mtDNA deletions and duplications events was observed at 7 days’ post-partum. Median heteroplasmy increased at one year of life and then returned to baseline by six years of age. The mtDNA instability was acquired and was not transmitted by the mother. No risk factors were significantly associated with mtDNA instability. In this small case series, we did not detect any association between any health outcome at 6 years and mtDNA instability measures. A significant effect modification of the association between the duration of maternal prophylaxis and child growth was observed after stratification with heteroplasmy rate. Genomic instability persists over time among HEU children but, despite its extension, stays subclinical at six years.
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