NRF1 mitigates motor dysfunction and dopamine neuron degeneration in mice with Parkinson's disease by promoting GLRX m6 A methylation through upregulation of METTL3 transcription

Abstract

Objective: The feature of Parkinson's disease (PD) is the heavy dopaminergic neuron loss of substantia nigra pars compacta (SNpc), while glutaredoxin (GLRX) has been discovered to modulate the death of dopaminergic neurons. In this context, this study was implemented to uncover the impact of GRX1 on motor dysfunction and dopamine neuron degeneration in PD mice and its potential mechanism.

Methods: A PD mouse model was established via injection with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into mice. After gain- and loss-of-function assays in mice, motor coordination was assessed using rotarod, pole, and open-field tests, and neurodegeneration in mouse SNpc tissues was determined using immunohistochemistry of tyrosine hydroxylase and Nissl staining. NRF1, methyltransferase-like 3 (METTL3), and GLRX expression in SNpc tissues were evaluated using qRT-PCR, Western blot, and immunohistochemistry. The N6-methyladenosine (m⁶ A) levels of GLRX mRNA were examined using MeRIP. The relationship among NRF1, METTL3, and GLRX was determined by RIP, ChIP, and dual luciferase assays.

Results: Low GLRX, METTL3, and NRF1 expression were observed in MPTP-induced mice, accompanied by decreased m⁶ A modification level of GLRX mRNA. GLRX overexpression alleviated motor dysfunction and dopamine neuron degeneration in MPTP-induced mice. METTL3 promoted m⁶ A modification and IGF2BP2-dependent stability of GLRX mRNA, and NRF1 increased METTL3 expression by binding to METTL3 promoter. NRF1 overexpression increased m⁶ A modification of GLRX mRNA and repressed motor dysfunction and dopamine neuron degeneration in MPTP-induced mice, which was counteracted by METTL3 knockdown.

Conclusion: Conclusively, NRF1 constrained motor dysfunction and dopamine neuron degeneration in MPTP-induced PD mice by activating the METTL3/GLRX axis.

Keywords: IGF2BP2; Parkinson's disease; dopamine neuron degeneration; glutaredoxin; m6A methylation; methyltransferase-like 3; motor dysfunction; nuclear factor erythroid 2-like 1.