The NONRATT023402.2/rno-miR-3065-5p/NGFR axis affects levodopa-induced dyskinesia in a rat model of Parkinson's disease

Levodopa-induced dyskinesia (LID) is a common motor complication in Parkinson's disease. However, few studies have focused on the pathogenesis of LID at the transcriptional level. NONRATT023402.2, a long non-coding RNA (lncRNA) that may be related to LID was discovered in our previous study and characterized in rat models of LID. In the present study, NONRATT023402.2 was overexpressed by injection of adeno-associated virus (AAV) in striatum of LID rats, and 48 potential target genes, including nerve growth factor receptor (NGFR) were screened using next-generation sequencing and target gene predictions. The NONRATT023402.2/rno-miR-3065-5p/NGFR axis was verified using a dual luciferase reporter gene. Overexpression of NONRATT023402.2 significantly increased the abnormal involuntary movements (AIM) score of LID rats, activated the PI3K/Akt signaling pathway, and up-regulated c-Fos in the striatum. NGFR knockdown by injection of ShNGFR-AAV into the striatum of LID rats resulted in a significant decrease in the PI3K/Akt signaling pathway and c-Fos expression. The AIM score of LID rats was positively correlated with the expressions of NONRATT023402.2 and NGFR. A dual luciferase reporter assay showed that c-Fos, as a transcription factor, bound to the NONRATT023402.2 promoter and activated its expression. Together, the results showed that NONRATT023402.2 regulated NGFR expression via a competing endogenous RNA mechanism, which then activated the PI3K/Akt pathway and promoted c-Fos expression. This suggested that c-Fos acted as a transcription factor to activate NONRATT023402.2 expression, and form a positive feedback regulation loop in LID rats, thus, aggravating LID symptoms. NONRATT023402.2 is therefore a possible novel therapeutic target for LID.