Nur77 exacerbates PC12 cellular injury in vitro by aggravating mitochondrial impairment and endoplasmic reticulum stress.
The nuclear orphan receptor, Nur77 plays important roles in neuroimflammation, apoptosis, and dopaminergic neurodegeneration. We conducted a further mechanistic investigation into the association of Nur77 with cell death. Cytosporone B (Csn-B), an agonist for Nur77, and Nur77 knockdown were adopted in the 6-hydroxydopamine (OHDA)-lesioned PC12 cells to investigate the mechanisms underlying Nur77-mediated injury. The 6-OHDA incubation caused Nur77 translocation from the nucleus to cytosol and Endoplasm reticulum (ER) and induced co-localization of Tom20/Nur77 and Protein Disulfide Isomerase (PDI)/Nur77. Nur77 activation further decreased cell viability, aggravated intracellular LDH release, intracellular Ca2+, ROS levels, apoptosis, ER tress and, mitochondrial transmembrane potential (ΔΨm) decline. In addition, Nur77 activation significantly enhanced the efficiency of autophagy as indicated by an up-regulation of Beclin-1/LC-3 and downregulation of p62, and aggravated mitochondrial dysfunctions and ER stress as shown by increased HSP60/Cytochrome C (Cyt C) and CHOP-ATF3 levels respectively. These changes could be partially reversed by Nur77 knockdown. Moreover, Nur77 activation upregulated PINK1 and downregulated Parkin levels. We conclude that Nur77 exacerbates PC12 cell death at least partially by aggravating the mitochondrial impairment and ER stress and enhancing autophagy. We propose that Nur77 is likely a critical target in the PD therapy.
Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Tianhe Road 600, Guangzhou, Guangdong 510630, P.R. China.
Huimin
H
Gao
Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Tianhe Road 600, Guangzhou, Guangdong 510630, P.R. China.
Zhaoyu
Z
Chen
Department of Emergency, The Third Affiliated Hospital of Sun Yat-Sen University, Tianhe Road 600, Guangzhou, Guangdong 510630, P.R. China.
Yongmei
Y
Fu
Department of Emergency, The Third Affiliated Hospital of Sun Yat-Sen University, Tianhe Road 600, Guangzhou, Guangdong 510630, P.R. China.
Xiaoyan
X
Yang
Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Tianhe Road 600, Guangzhou, Guangdong 510630, P.R. China.
Ruihui
R
Weng
Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Tianhe Road 600, Guangzhou, Guangdong 510630, P.R. China.
Rui
R
Wang
Department of Neurology, Guangdong 999 Brain Hospital, Guangzhou 510510, China.
Jianjun
J
Lu
Department of Neurology, Guangdong 999 Brain Hospital, Guangzhou 510510, China.
Mengqiu
M
Pan
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Kunlin
K
Jin
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Chris
C
McElroy
The State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078, China.
Beisha
B
Tang
Department of Neurosurgery, The University of Texas McGovern Medical School, TX 77030, USA.
Ying
Y
Xia
Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Tianhe Road 600, Guangzhou, Guangdong 510630, P.R. China.|Guangdong Province Key Laboratory of Brain Function and Disease, Guangzhou, Guangdong, P.R. China.
Qing
Q
Wang
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