HOTAIR Accelerates Dyskinesia in a MPTP-Lesioned Mouse Model of PD via SSTR1 Methylation-Mediated ERK1/2 Axis

Homeobox transcript antisense RNA (HOTAIR), has been associated with neuroprotective effects in Parkinson’s disease (PD). However, the underlying mechanisms still remain unclear. Hence, this present study attempted to clarify the functional relevance of HOTAIR in PD. We established an in vivo mouse model of PD using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and an in vitro cell model of PD by treating dopaminergic neuron MN9D cells with 1-methyl-4-phenylpyridinium species (MPP(+)). The expressions of somatostatin receptor 1 (SSTR1) and HOTAIR were altered to examine their effects on MN9D cell viability and apoptosis, as well as on movement impairments in MPTP-induced PD mouse model. The results indicated that HOTAIR expression was upregulated and SSTR1 was downregulated in in vivo and in vitro PD models. HOTAIR could bind to the promoter region of SSTR1, resulting in an increase of SSTR1 methylation through the recruitment of DNA methyltransferases in PD cell models. Notably, overexpression of HOTAIR and silencing of SSTR1 enhanced dopaminergic neuron apoptosis in MN9D cells and exacerbated dyskinesia in MPTP-induced PD mouse model. Collectively, overexpressed HOTAIR stimulates DNA methylation of SSTR1 to reduce SSTR1 expression, thereby accelerating dyskinesia and facilitating dopaminergic neuron apoptosis in a MPTP-lesioned PD mouse model via activation of the ERK1/2 axis.