Estrogen receptor activation contributes to RNF146 expression and neuroprotection in Parkinson's disease models

Abstract

RNF146 is an E3 ubiquitin ligase that specifically recognizes and polyubiquitinates poly (ADP-ribose) (PAR)-conjugated substrates for proteasomal degradation. RNF146 has been shown to be neuroprotective against PAR polymerase-1 (PARP1)-induced cell death during stroke. Here we report that RNF146 expression and RNF146 inducers can prevent cell death elicited by Parkinson’s disease (PD)-associated and PARP1-activating stimuli. In SH-SY5Y cells, RNF146 expression conferred resistance to toxic stimuli that lead to PARP1 activation. High-throughput screen using a luciferase construct harboring the RNF146 promoter identified liquiritigenin as an RNF146 inducer. We found that RNF146 expression by liquiritigenin was mediated by estrogen receptor activation and contributed to cytoprotective effect of liquiritigenin. Finally, RNF146 expression by liquiritigenin in mouse brains provided dopaminergic neuroprotection in a 6-hydroxydopamine PD mouse model. Given the presence of PARP1 activity and RNF146 deficits in PD, it could be a potential therapeutic strategy to restore RNF146 expression by natural compounds or estrogen receptor activation.

Phytochemical and Pharmacological Role of Liquiritigenin and Isoliquiritigenin From Radix Glycyrrhizae in Human Health and Disease Models

“…Similarly, CRISPR-Cas9–mediated ERβ ablation eliminated the LG-induced neuroprotection against H 2 O 2 toxicity. Taken together, these data indicate that LG-induced activations of ERβ and RNF146 inhibit PARP1 and confer neuroprotection ( Kim et al, 2017 ).…”

“…Tamoxifen, an ER antagonist, blocked the LG-induced increase in RNF146 expression, indicating that ER activation was responsible for RNF146 induction. In addition, LG failed to induce RNF146 expression in an ERβ deletion model ( Kim et al, 2017 ).…”

“…In a model of H 2 O 2 toxicity, primary mouse cortical neurons exposed to LG showed a 4-fold increase in RNF146 expression and reversed cellular ATP content and mitochondrial membrane potential. H 2 O 2 induces robust PARP1 activation, which was largely abolished by LG treatment ( Kim et al, 2017 ). AIMP2, a parkin substrate, enhances cell toxicity, and the levels of PAR-conjugated proteins were significantly reduced by LG-induced RNF146 expression.…”

“…In a 6-OHDA–induced PD-like model, LG pretreatment markedly enhanced tyrosine hydroxylase (TH)-positive DArgic neurons and almost completely inhibited PARP1 activity. Moreover, LG was shown to selectively activate ERβ, but not ERα, thus avoiding aberrant tumor growth in vivo ( Mersereau et al, 2008 ) and improving the safety profile of long-term LG treatment for NDDs ( Kim et al, 2017 ). Therefore, ILG and LG are potential candidates against PD in in vitro and in vivo models and their working mechanisms are diagrammatically represented in Figure 1 .…”

Roles of aminoacyl-tRNA synthetase-interacting multi-functional proteins in physiology and cancer

“…Interestingly, accumulating evidence has identified that AIMPs participate in various physiological and pathological processes as multifaceted molecules 10 – 13 . It was reported that the downregulation of AIMP1 enhanced transforming growth factor-β (TGF-β) signal by inducing the phosphorylation of Smad family member 2/3 (Smad2/3), which in turn promoted the chondrogenic potential of dedifferentiated/degenerated chondrocytes 14 .…”