Objective: To investigate the correlation between telomere length (TL) and Parkinson’s disease (PD), and whether the change in telomere biology participates in PD pathogenesis.

Background: Mitochondrial damage and telomere dysfunctions, two aging hallmarks, share intimate links and have important roles in human neurodegenerative diseases, especially Alzheimer’s disease (AD) and PD. In clinical studies, telomere shortening in blood cells correlates with a decreased life expectancy and increased risk of AD, but its correlation with PD remains inconclusive. Besides, there is increasing evidence that chaperones/chaperonins participate in the pathogenesis of PD, while a detailed mechanism is warranted to confirm.

Method: To investigate TL in the Taiwanese cohort, a follow-up measurement of PBMC is performed by qPCR, and an examination of iPSC is performed by Southern blot. Telomerase components are examined by Western blot and RT-qPCR. To identify key factors in both LRRK2- and UQCRC1-associated Parkinson’s disease, mass spectrometer-based quantitative proteomics analysis is applied. To investigate whether the altered expression of chaperonins, the CCT complex, affects the process of recruiting and assembling telomerase in the Cajal bodies (CBs) for telomere elongation, the RNA FISH is carried out.

Results: In this study, the majority of sporadic PD patients exhibited shorter telomeres. Interestingly, longer TLs are seen in PD patients carrying a mutation in PD genes, including UQCRC1, LRRK2, Parkin, PLA2G6, PINK1, and DNAJC13. Supporting these observations, iPSCs carrying a mutation in UQCRC1 or LRRK2 gene exhibit longer telomeres compared to the corresponding control cells. Biochemical experiments show increased levels of telomerase components in PD iPSCs. In addition, UQCRC1_Y314S mutation facilitates telomerase RNA (hTR) biogenesis. Proteomic analysis of UQCRC1 and LRRK2 mutant cells highlights a common pathway related to the CCT complex, which could cause an increased proportion of hTR in CBs in UQCRC1_Y314S iPS cells, therefore leading to telomere elongation.

Conclusion: My findings show that the UQCRC1 mutation causes telomere elongation, and upregulation of some telomerase components, and the CCT complex partially explain the longer TL expressed in PD. These results provide additional links between telomere biology and PD caused by gene mutation, at least LRRK2 and UQCRC1.

« Back to 2023 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/impacts-of-mutations-in-parkinsons-disease-related-genes-on-telomere-maintenance/