Multiplication of the SNCA locus exacerbates neuronal nuclear aging.
Journal Article (Journal Article)
Human-induced Pluripotent Stem Cell (hiPSC)-derived models have advanced the study of neurodegenerative diseases, including Parkinson's disease (PD). While age is the strongest risk factor for these disorders, hiPSC-derived models represent rejuvenated neurons. We developed hiPSC-derived Aged dopaminergic and cholinergic neurons to model PD and related synucleinopathies. Our new method induces aging through a `semi-natural' process, by passaging multiple times at the Neural Precursor Cell stage, prior to final differentiation. Characterization of isogenic hiPSC-derived neurons using heterochromatin and nuclear envelope markers, as well as DNA damage and global DNA methylation, validated our age-inducing method. Next, we compared neurons derived from a patient with SNCA-triplication (SNCA-Tri) and a Control. The SNCA-Tri neurons displayed exacerbated nuclear aging, showing advanced aging signatures already at the Juvenile stage. Noteworthy, the Aged SNCA-Tri neurons showed more α-synuclein aggregates per cell versus the Juvenile. We suggest a link between the effects of aging and SNCA overexpression on neuronal nuclear architecture.
- Tagliafierro, L; Zamora, ME; Chiba-Falek, O
- February 1, 2019
Volume / Issue
- 28 / 3
Start / End Page
- 407 - 421
Pubmed Central ID
Electronic International Standard Serial Number (EISSN)
Digital Object Identifier (DOI)