Protein arginine methyltransferase-1 stimulates dopaminergic neuronal cell death in a Parkinson’s disease model

• Published in: Biochemical and biophysical research communications 2020-09, Vol.530 (2), p.389-395
• Main Authors: Nho, Jong-Hyun, Park, Min-Jung, Park, Hyung Joon, Lee, Jin Ho, Choi, Joo-Hee, Oh, Sang-Jin, Lee, Young-Jin, Yu, Young-Beob, Kim, Hyung-Seok, Kim, Dong-il, Choi, Won-Seok
• Format: Article
• Language: English
• Subjects: AIF; Animals; Cell Death; Disease Models, Animal; Dopaminergic neuronal death; Dopaminergic Neurons - metabolism; Dopaminergic Neurons - pathology; Humans; Male; Mice; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson’s disease; PARP1; Parthanatos; PRMT1; Protein-Arginine N-Methyltransferases - analysis; Protein-Arginine N-Methyltransferases - metabolism
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2020.05.016

Recent studies have revealed that protein arginine methyltransferases (PRMTs) are responsible for diverse neurodegenerative diseases. However, their pathophysiological role in dopaminergic neuronal death in Parkinson’s disease (PD) has not been evaluated. In this study, we demonstrated that 1-Methyl-4-phenylpyridinium iodide (MPP+), rotenone and paraquat, which cause dopaminergic neuronal cell death, increased PRMT1 expression in dopaminergic cell line. Dopaminergic neuronal cell death was increased by PRMT1 overexpression. MPP+-induced cell death was attenuated by PRMT1 knockdown. Poly (ADP-ribose) polymerase-1 (PARP1) expression and activity, poly-ADP-ribosylation (PARylation), were elevated by MPP+. Moreover, we found that PRMT1 positively regulates nuclear translocation of apoptosis-inducing factor (AIF). Elevated PRMT1 expression was observed in the substantia nigra pars compacta of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-injected mice. Furthermore, MPTP-induced dopaminergic neuronal death was reduced in PRMT1 haploinsufficient (prmt1+/−) mice. These data suggest that PRMT1 is implicated in PARP1/AIF-mediated dopaminergic neuronal cell death, which might be involved in the pathology of PD. Therefore, our results propose PRMT1 as a new target to develop a potential treatment of PD. •PRMT1 expression is elevated in dopaminergic neuronal cell death.•Reduction of PRMT1 and PART1 inhibition prevent dopaminergic cell death.•PRMT1 mediates nuclear translocation of AIF.