This in vitro study shows that a protein encoded by circFKBP8(5S,6) (cFKBP8) is upregulated in MPP+-treated SH-SY5Y cells and that cFKBP8 overexpression raises while its silencing lowers α-synuclein levels.

Points to a novel circRNA-encoded protein that directly modulates α-synuclein, offering a potential biomarker or therapeutic target for PD, but findings are preliminary and need in vivo and human validation.

BACKGROUND: Parkinson’s disease (PD) is the second most common neurodegenerative disease globally, characterized by the abnormal aggregation of α-synuclein. Recent studies suggest that circular RNAs (circRNAs), predominantly formed by back-splicing of pre-mRNAs, and the proteins they encode are implicated in neurodegenerative diseases; however, the specific role of circular RNA-encoded proteins in PD is understudied. This study investigated the expression and functional role of the circFKBP8(5S,6)-encoded protein (cFKBP8), translated from the circular RNA circFKBP8(5S,6), in a cellular model of PD. METHODS AND RESULTS: An in vitro PD model was created by treating SH-SY5Y cells with 1-methyl-4-phenylpyridinium (MPP⁺). cFKBP8 expression was assessed using immunofluorescence staining and quantitative real-time polymerase chain reaction (RT-qPCR). An increase in cFKBP8 expression was found in MPP⁺-treated cells compared to untreated controls. Functional analyses using Western blot revealed that cFKBP8 overexpression significantly increased α-synuclein expression. In contrast, silencing cFKBP8 decreased α-synuclein levels in SH-SY5Y cells. CONCLUSIONS: These results indicate that cFKBP8 expression is increased in a cellular model of PD and can influence α-synuclein expression in SH-SY5Y cells, thereby highlighting the role of circRNA-encoded proteins in α-synuclein biology, with potential implications for developing biomarkers and therapeutic strategies for PD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11033-026-11723-z.