Ubiquitin ligase HMG-CoA reductase degradation 1 (HRD1) prevents cell death in a cellular model of Parkinson's disease

Tomohiro Omura, Hiroki Matsuda, Luna Nomura, Satoshi Imai, Masaya Denda, Shunsaku Nakagawa, Atsushi Yonezawa, Takayuki Nakagawa, Ikuko Yano, Kazuo Matsubara

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

Endoplasmic reticulum (ER) stress may play a role in the etiology of Parkinson's disease (PD). We have previously reported that ubiquitin ligase 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase degradation 1 (HRD1) involved in ER stress degrades unfolded protein that accumulates in the ER due to loss of function of Parkin, which is a causative factor in familial PD. We have also demonstrated that cell death is suppressed by the degradation of unfolded proteins. These findings indicate that HRD1 may serve as a compensatory mechanism for the loss of function of Parkin in familial PD patients. However, the role of HRD1 in sporadic PD has not yet been identified. This study aimed to reveal the roles of HRD1 and associated molecules in a cellular model of PD. We demonstrated that expressions of HRD1 and Suppressor/Enhancer Lin12 1-like (SEL1L: a HRD1 stabilizer) increased in SH-SY5Y human neuroblastoma cells upon exposure to 6-hydroxydopamine (6-OHDA). The 6-OHDA-induced cell death was suppressed in cells overexpressing wt-HRD1, whereas cell death was enhanced in cells with knockdown of HRD1 expression. These results suggest that HRD1 is a key molecule involved in 6-OHDA-induced cell death. By contrast, suppression of SEL1L expression decreased the amount of HRD1 protein. As a result, 6-OHDA-induced cell death was enhanced in cells suppressing SEL1L expression, and this cell death was much more evident than that in cells with suppression of HRD1 expression. These findings strongly indicate that SEL1L is necessary for maintaining and stabilizing the amount of HRD1 protein, and stabilizing the amount of HRD1 protein through SEL1L may serve to protect against 6-OHDA-induced cell death. Furthermore, the expression of Parkin was reinforced when HRD1 mRNA had been suppressed in cells, but was not observed when SEL1L mRNA had been restrained. It is possible that Parkin expression is induced as a compensatory mechanism when HRD1 mRNA decreases. This intracellular transduction may suppress the enhancement of 6-OHDA-induced cell death caused by the loss of HRD1. Taken together with these results, it is suggested that HRD1 and its stabilizer (SEL1L) are key molecules for elucidating the pathogenesis and treatment of PD.

Original languageEnglish
Pages (from-to)516-521
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume506
Issue number3
DOIs
Publication statusPublished - 2018 Nov 30
Externally publishedYes

Keywords

  • ER stress
  • HRD1
  • Parkin
  • Parkinson's disease (PD)
  • Ubiquitin ligase (E3)

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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