A53T α-Synuclein Expression is Associated with Altered Dopaminergic-Like Differentiation and Reduced DNA Topoisomerase IIβ Levels in an In Vitro Model of Parkinson's Disease.

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The study explores the interaction between topoisomerase IIβ (topo IIβ) and α-synuclein aggregation in Parkinson's disease (PD) using an in vitro model overexpressing A53T mutant α-synuclein, revealing key pathological features. The overexpression of A53T mutant α-synuclein was associated with impaired neuronal differentiation, accompanied by delayed neurite outgrowth and reduced levels of MAP2 and NF-L. Transcriptomic study during differentiation revealed substantial gene expression changes, with 57 of 84 PD-associated genes exhibiting differential regulation on days 8 and 12. Dopaminergic markers like TH, BDNF, NR4A2 (Nurr1), PINK1, and SYNGR3 were notably upregulated in differentiated cells, whereas A53T mutant α-synuclein overexpression was associated with significant downregulation of 22 genes associated with PD, including TH, NR4A2, BDNF, and PINK1, suggesting alterations in neuroprotective signaling pathways. Topo IIβ expression diminished during differentiation in the presence of pathogenic α-synuclein and was associated with changes in the proposed topo IIβ-Nurr1 regulatory axis potentially contributing to early neurodevelopmental abnormalities and dopaminergic vulnerability observed in PD.

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