Deficiency of RAB39B Activates ER Stress-Induced Pro-apoptotic Pathway and Causes Mitochondrial Dysfunction and Oxidative Stress in Dopaminergic Neurons by Impairing Autophagy and Upregulating α-Synuclein

被引：7

作者：

Chiu, Ching-Chi ^{[1
,2
,3
]}

Weng, Yi-Hsin ^{[2
,4
,5
]}

Yeh, Tu-Hsueh ^{[6
]}

Lu, Juu-Chin ^{[7
]}

Chen, Wan-Shia ^{[7
]}

Li, Allen Han-Ren ^{[8
]}

Chen, Ying-Ling ^{[9
]}

Wei, Kuo-Chen ^{[2
,10
]}

Wang, Hung-Li ^{[2
,3
,4
,7
]}

机构：

[1] Chang Gung Univ, Dept Med Biotechnol & Lab Sci, Coll Med, Taoyuan, Taiwan

[2] Chang Gung Mem Hosp Linkou, Neurosci Res Ctr, Taoyuan, Taiwan

[3] Chang Gung Univ, Hlth Aging Res Ctr, Coll Med, Taoyuan, Taiwan

[4] Chang Gung Mem Hosp Linkou, Dept Neurol, Div Movement Disorders, Taoyuan, Taiwan

[5] Chang Gung Univ, Coll Med, Taoyuan, Taiwan

[6] Taipei Med Univ Hosp, Dept Neurol, Taipei, Taiwan

[7] Chang Gung Univ, Dept Physiol & Pharmacol, Coll Med, 259,Wen Hwa 1St Rd, Taoyuan 333, Taiwan

[8] Chang Gung Mem Hosp Linkou, Dept Anesthesiol, Taoyuan, Taiwan

[9] Chang Gung Univ Sci & Technol, Dept Nursing, Taoyuan, Taiwan

[10] Chang Gung Mem Hosp Linkou, Dept Neurosurg, Taoyuan, Taiwan

来源：

MOLECULAR NEUROBIOLOGY | 2023年 / 60卷 / 05期

关键词：

RAB39B; Dopaminergic neurons; Autophagy; alpha-Synuclein; ER stress; Mitochondria; UNFOLDED PROTEIN RESPONSE; PARKINSONS-DISEASE; INTELLECTUAL DISABILITY; HEXANUCLEOTIDE REPEAT; CELL-DEATH; RAT MODEL; MUTATIONS; NEURODEGENERATION; PHOSPHORYLATION; C9ORF72;

D O I：

10.1007/s12035-023-03238-6

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Deletion and missense or nonsense mutation of RAB39B gene cause familial Parkinson's disease (PD). We hypothesized that deletion and mutation of RAB39B gene induce degeneration of dopaminergic neurons by decreasing protein level of functional RAB39B and causing RAB39B deficiency. Cellular model of deletion or mutation of RAB39B gene-induced PD was prepared by knocking down endogenous RAB39B in human SH-SY5Y dopaminergic cells. Transfection of shRNA-induced 90% reduction in RAB39B level significantly decreased viability of SH-SY5Y dopaminergic neurons. Deficiency of RAB39B caused impairment of macroautophagy/autophagy, which led to increased protein levels of alpha-synuclein and phospho-alpha-synuclein(Ser129) within endoplasmic reticulum (ER) and mitochondria. RAB39B deficiency-induced increase of ER alpha-synuclein and phospho-alpha-synuclein(Ser129) caused activation of ER stress, unfolded protein response, and ER stress-induced pro-apoptotic cascade. Deficiency of RAB39B-induced increase of mitochondrial alpha-synuclein decreased mitochondrial membrane potential and increased mitochondrial superoxide. RAB39B deficiency-induced activation of ER stress pro-apoptotic pathway, mitochondrial dysfunction, and oxidative stress caused apoptotic death of SH-SY5Y dopaminergic cells by activating mitochondrial apoptotic cascade. In contrast to neuroprotective effect of wild-type RAB39B, PD mutant (T168K), (W186X), or (G192R) RAB39B did not prevent tunicamycin- or rotenone-induced increase of neurotoxic alpha-synuclein and activation of pro-apoptotic pathway. Our results suggest that RAB39B is required for survival and macroautophagy function of dopaminergic neurons and that deletion or PD mutation of RAB39B gene-induced RAB39B deficiency induces apoptotic death of dopaminergic neurons via impairing autophagy function and upregulating alpha-synuclein.

引用

页码：2706 / 2728

页数：23

共 1 条

[1] Deficiency of RAB39B Activates ER Stress-Induced Pro-apoptotic Pathway and Causes Mitochondrial Dysfunction and Oxidative Stress in Dopaminergic Neurons by Impairing Autophagy and Upregulating α-Synuclein
Ching-Chi Chiu
Yi-Hsin Weng
Tu-Hsueh Yeh
Juu-Chin Lu
Wan-Shia Chen
Allen Han-Ren Li
Ying-Ling Chen
Kuo-Chen Wei
Hung-Li Wang
Molecular Neurobiology, 2023, 60 : 2706 - 2728

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