Genetics Influences Telomere Length in Parkinson's Disease: A Study in Monozygotic Discordant Twins

Background: Parkinson's disease (PD) results from complex interactions among environmental, genetic, and aging factors. Telomeres, which ensure chromosome stability, naturally shorten with cell division, contributing to aging and cellular senescence. However, studies investigating telomere length (TL) in PD have produced inconsistent results. Objective: This study aims to explore the relationship between TL and PD using a unique PD-discordant monozygotic twin design, which minimizes confounding factors such as age, gender, and genetic background. We also examined the impact of PD-related genetic mutations on TL. Methods: We analyzed relative telomere length (RTL) in blood samples from 29 pairs of monozygotic twins discordant for PD. Data was stratified by disease duration, and we investigated the influence of genetic variants (GBA1 and LRRK2) on RTL. Results: No significant difference in RTL was observed between PD-affected twins and their healthy co-twins overall. However, twins with longer disease duration (≥8 years) showed a significant decline in RTL (0.90 ± 0.18 vs. 1.07 ± 0.24; P = 0.046), which was more pronounced with a 10-year disease duration cutoff (0.85 ± 0.18 vs. 1.06 ± 0.22; P = 0.015). GBA1-mutated PD twins exhibited significantly longer RTL than non-mutated twins, a result replicated in non-twin GBA1 carriers and extended to LRRK2 carriers. Conclusions: Our findings suggest that aging and cellular senescence primarily drive sporadic PD, whereas genetic forms are linked to disruptions in cellular pathways, such as lysosomal or mitochondrial functions. These insights highlight the role of genetics in telomere dynamics in PD.