Long non-coding RNA GAS5 promotes neuronal apoptosis in spinal cord injury via the miR-21/PTEN axis.

Abstract

Background: Spinal cord injury (SCI) is a severe and permanent trauma that often leads to significant motor, sensory, and autonomic dysfunction. Neuronal apoptosis is a major pathomechanism underlying secondary injury in SCI. Long non-coding RNAs (lncRNAs) have emerged as key regulators of gene expression and cellular processes, including apoptosis. However, the role of lncRNA growth arrest-specific transcript 5 (GAS5) in SCI-induced neuronal apoptosis remains unclear.

Aim: To investigate the role of lncRNA GAS5 in SCI-induced neuronal apoptosis via its interaction with microRNA (miR)-21 and the phosphatase and tensin homolog (PTEN)/AKT pathway.

Methods: SCI rat models and hypoxic neuronal cell models were established. Motor function was assessed using the Basso-Beattie-Bresnahan score. Expression levels of GAS5, miR-21, PTEN, caspase 3, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), and AKT were measured using quantitative PCR or Western blot analysis. Neuronal apoptosis was determined by TUNEL staining. Dual-luciferase reporter assays validated GAS5-miR-21 binding. Knockdown and overexpression experiments explored the functional effects of the GAS5/miR-21 axis.

Results: GAS5 was significantly upregulated in the spinal cord following SCI, coinciding with increased neuronal apoptosis and decreased AKT activation. In vitro experiments demonstrated that GAS5 acted as a molecular sponge for miR-21, leading to increased PTEN expression and inhibition of the AKT signaling pathway, thereby promoting apoptosis. In vivo, GAS5 knockdown attenuated neuronal apoptosis, enhanced AKT activation, and improved motor function recovery in SCI rats.

Conclusion: GAS5 promotes neuronal apoptosis in SCI by binding to miR-21 and upregulating PTEN expression, inhibiting the AKT pathway. Targeting GAS5 may represent a novel therapeutic strategy for SCI.