Cell Type-Specific Upregulation of Parkin in Response to ER Stress

Wang, Hua–Qin; Imai, Yuzuru; Kataoka, Ayane; Takahashi, Ryōsuke

doi:10.1089/ars.2006.1522

Cited by 32 publications

(24 citation statements)

References 31 publications

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“…39 It was found that PARK2 is more prone to be upregulated by ER stress in neurons compared with other cell types. 44 Although the cell specific mechanisms were not fully elucidated, our data at least suggest that ER stress conferred brain protection in our model, may be largely due to its direct actions on neurons. In addition, we interestingly found that both Atf4 and Eif2s1 silencing reduced PARK2 expression in intact neurons in a dose-and time-dependent manner (Fig.…”

Section: Discussionmentioning

confidence: 73%

Endoplasmic reticulum stress induced by tunicamycin and thapsigargin protects against transient ischemic brain injury

Zhang¹,

et al. 2014

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Transient cerebral ischemia leads to endoplasmic reticulum (ER) stress. However, the contributions of ER stress to cerebral ischemia are not clear. To address this issue, the ER stress activators tunicamycin (TM) and thapsigargin (TG) were administered to transient middle cerebral artery occluded (tMCAO) mice and oxygen-glucose deprivation-reperfusion (OGD-Rep.)-treated neurons. Both TM and TG showed significant protection against ischemia-induced brain injury, as revealed by reduced brain infarct volume and increased glucose uptake rate in ischemic tissue. In OGD-Rep.-treated neurons, 4-PBA, the ER stress releasing mechanism, counteracted the neuronal protection of TM and TG, which also supports a protective role of ER stress in transient brain ischemia. Knocking down the ER stress sensor Eif2s1, which is further activated by TM and TG, reduced the OGD-Rep.-induced neuronal cell death. In addition, both TM and TG prevented PARK2 loss, promoted its recruitment to mitochondria, and activated mitophagy during reperfusion after ischemia. The neuroprotection of TM and TG was reversed by autophagy inhibition (3-methyladenine and Atg7 knockdown) as well as Park2 silencing. The neuroprotection was also diminished in Park2(+/-) mice. Moreover, Eif2s1 and downstream Atf4 silencing reduced PARK2 expression, impaired mitophagy induction, and counteracted the neuroprotection. Taken together, the present investigation demonstrates that the ER stress induced by TM and TG protects against the transient ischemic brain injury. The PARK2-mediated mitophagy may be underlying the protection of ER stress. These findings may provide a new strategy to rescue ischemic brains by inducing mitophagy through ER stress activation.

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Section: Discussionmentioning

confidence: 73%

Endoplasmic reticulum stress induced by tunicamycin and thapsigargin protects against transient ischemic brain injury

Zhang¹,

et al. 2014

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“…Previous studies do suggest a link between Parkin function and ER stress. Parkin expression is increased in response to ER stress (Wang et al, 2007), and accumulation of the Parkin substrate Pael-R leads to ER stress (Imai et al, 2001; Kitao et al, 2007). Further, findings by Yamamoto et al suggest that ER stress results in a decrease in the phosphorylation rate of Parkin concordant with an increase in ubiquitin ligase activity (Yamamoto et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Glutamate excitotoxicity in neurons triggers mitochondrial and endoplasmic reticulum accumulation of Parkin, and, in the presence of N-acetyl cysteine, mitophagy

Laar

Roy

Liu

et al. 2015

Neurobiology of Disease

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Disruption of the dynamic properties of mitochondria (fission, fusion, transport, degradation, and biogenesis) has been implicated in the pathogenesis of neurodegenerative disorders, including Parkinson’s disease (PD). Parkin, the product of gene PARK2 whose mutation causes familial PD, has been linked to mitochondrial quality control via its role in regulating mitochondrial dynamics, including mitochondrial degradation via mitophagy. Models using mitochondrial stressors in numerous cell types have elucidated a PINK1-dependent pathway whereby Parkin accumulates on damaged mitochondria and targets them for mitophagy. However, the role Parkin plays in regulating mitochondrial homeostasis specifically in neurons has been less clear. We examined whether a stressor linked to neurodegeneration, glutamate excitotoxicity, elicits Parkin-mitochondrial translocation and mitophagy in neurons. We found that brief, acute exposure to glutamate causes Parkin translocation to mitochondria in neurons, in a calcium- and N-methyl-D-aspartate (NMDA) receptor-dependent manner. In addition, we found that Parkin accumulates on endoplasmic reticulum (ER) and mitochondrial/ER junctions following excitotoxicity, supporting a role for Parkin in mitochondrial-ER crosstalk in mitochondrial homeostasis. Despite significant Parkin-mitochondria translocation, however, we did not observe mitophagy under these conditions. To further investigate, we examined the role of glutamate-induced oxidative stress in Parkin-mitochondria accumulation. Unexpectedly, we found that glutamate-induced accumulation of Parkin on mitochondria was promoted by the antioxidant N-acetyl cysteine (NAC), and that co-treatment with NAC facilitated Parkin-associated mitophagy. These results suggest the possibility that mitochondrial depolarization and oxidative damage may have distinct pathways associated with Parkin function in neurons, which may be critical in understanding the role of Parkin in neurodegeneration.

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“…Of note, no or only a few positive control images are shown in most articles, hindering the comparative literature survey. Also, SH-SY5Y cells are known to respond inconsistently to the same differentiation treatment, depending on their cell source [49] or possibly passage number. Therefore, the variation reported may be at least in part due to the origin of the cells and different aspects regarding their handling, highlighting the importance of the proper reporting of all protocols involved.…”

Section: Main Textmentioning

confidence: 99%

The SH-SY5Y cell line in Parkinson’s disease research: a systematic review

Xicoy

Wieringa

Martens

2017

Mol Neurodegeneration

730

589

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Parkinson’s disease (PD) is a devastating and highly prevalent neurodegenerative disease for which only symptomatic treatment is available. In order to develop a truly effective disease-modifying therapy, improvement of our current understanding of the molecular and cellular mechanisms underlying PD pathogenesis and progression is crucial. For this purpose, standardization of research protocols and disease models is necessary. As human dopaminergic neurons, the cells mainly affected in PD, are difficult to obtain and maintain as primary cells, current PD research is mostly performed with permanently established neuronal cell models, in particular the neuroblastoma SH-SY5Y lineage. This cell line is frequently chosen because of its human origin, catecholaminergic (though not strictly dopaminergic) neuronal properties, and ease of maintenance. However, there is no consensus on many fundamental aspects that are associated with its use, such as the effects of culture media composition and of variations in differentiation protocols. Here we present the outcome of a systematic review of scientific articles that have used SH-SY5Y cells to explore PD. We describe the cell source, culture conditions, differentiation protocols, methods/approaches used to mimic PD and the preclinical validation of the SH-SY5Y findings by employing alternative cellular and animal models. Thus, this overview may help to standardize the use of the SH-SY5Y cell line in PD research and serve as a future user’s guide.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-017-0149-0) contains supplementary material, which is available to authorized users.

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Cell Type-Specific Upregulation of Parkin in Response to ER Stress

Cited by 32 publications

References 31 publications

Endoplasmic reticulum stress induced by tunicamycin and thapsigargin protects against transient ischemic brain injury

Endoplasmic reticulum stress induced by tunicamycin and thapsigargin protects against transient ischemic brain injury

Glutamate excitotoxicity in neurons triggers mitochondrial and endoplasmic reticulum accumulation of Parkin, and, in the presence of N-acetyl cysteine, mitophagy

The SH-SY5Y cell line in Parkinson’s disease research: a systematic review

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