Proteasome inhibitor-induced autophagy in PC12 cells overexpressing A53T mutant α-synuclein

Lan, Dan-Mei; Wang, Wenzhao; Zhuang, Jianhua; Zhao, Zhiguang

doi:10.3892/mmr.2014.3011

Cited by 38 publications

(35 citation statements)

References 30 publications

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“…Consistent with other reports (Lan et al, 2015;Tang et al, 2014), analysis of the autophagosome marker LC3-II showed that proteasomal inhibition promoted enhancement of the autophagic flux. Silencing of LAMP3 impaired the induction of autophagic flux and promoted cell death.…”

Section: Discussionsupporting

confidence: 89%

Loss of lysosome-associated membrane protein 3 (LAMP3) enhances cellular vulnerability against proteasomal inhibition

Domínguez-Bautista

Klinkenberg

Brehm

et al. 2015

European Journal of Cell Biology

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The family of lysosome-associated membrane proteins (LAMP) includes the ubiquitously expressed LAMP1 and LAMP2, which account for half of the proteins in the lysosomal membrane. Another member of the LAMP family is LAMP3, which is expressed only in certain cell types and differentiation stages. LAMP3 expression is linked with poor prognosis of certain cancers, and the locus where it is encoded was identified as a risk factor for Parkinson's disease (PD). Here, we investigated the role of LAMP3 in the two main cellular degradation pathways, the proteasome and autophagy. LAMP3 mRNA was not detected in mouse models of PD or in the brain of human patients. However, it was strongly induced upon proteasomal inhibition in the neuroblastoma cell line SH-SY5Y. Induction of LAMP3 mRNA following proteasomal inhibition was dependent on UPR transcription factor ATF4 signaling and induced autophagic flux. Prevention of LAMP3 induction enhanced apoptotic cell death. In summary, these data demonstrate that LAMP3 regulation as part of the UPR contributes to protein degradation and cell survival during proteasomal dysfunction. This link between autophagy and the proteasome may be of special importance for the treatment of tumor cells with proteasomal inhibitors.

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Section: Discussionsupporting

confidence: 89%

Loss of lysosome-associated membrane protein 3 (LAMP3) enhances cellular vulnerability against proteasomal inhibition

Domínguez-Bautista

Klinkenberg

Brehm

et al. 2015

European Journal of Cell Biology

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“…As previously reported [77,36,78], inhibition of the proteasome with MG132 induces autophagy (Suppl. Fig.…”

Section: Resultssupporting

confidence: 72%

Inhibition of Protein Ubiquitination by Paraquat and 1-Methyl-4-Phenylpyridinium Impairs Ubiquitin-Dependent Protein Degradation Pathways

et al. 2015

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Intracytoplasmic inclusions of protein aggregates in dopaminergic cells (Lewy bodies) are the pathological hallmark of Parkinson’s disease (PD). Ubiquitin (Ub), alpha [α]-synuclein, p62/sequestosome 1 and oxidized proteins are major components of Lewy bodies. However, the mechanisms involved in the impairment of misfolded/oxidized protein degradation pathways in PD are still unclear. PD is linked to mitochondrial dysfunction and environmental pesticide exposure. In this work, we evaluated the effect of the pesticide paraquat (PQ) and the mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP+) on Ub-dependent protein degradation pathways. No increase in the accumulation of Ub-bound proteins or aggregates was observed in dopaminergic cells (SK-N-SH) treated with PQ or MPP+, or in mice chronically exposed to PQ. PQ decreased Ub protein content, but not its mRNA transcription. Protein synthesis inhibition with cycloheximide depleted Ub levels and potentiated PQ–induced cell death. Inhibition of proteasomal activity by PQ was found to be a late event in cell death progression, and had no effect on either the toxicity of MPP+ or PQ, or the accumulation of oxidized sulfenylated, sulfonylated (DJ-1/PARK7 and peroxiredoxins) and carbonylated proteins induced by PQ. PQ- and MPP+-induced Ub protein depletion prompted the dimerization/inactivation of the Ub-binding protein p62 that regulates the clearance of ubiquitinated proteins by autophagic. We confirmed that PQ and MPP+ impaired autophagy flux, and that the blockage of autophagy by the overexpression of a dominant-negative form of the autophagy protein 5 (dnAtg5) stimulated their toxicity, but there was no additional effect upon inhibition of the proteasome. PQ induced an increase in the accumulation of α-synuclein in dopaminergic cells and membrane associated foci in yeast cells. Our results demonstrate that inhibition of protein ubiquitination by PQ and MPP+ is involved in the dysfunction of Ub-dependent protein degradation pathways.

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“…According to previous reports, the pathological changes in α-synuclein, such as its overexpression and formation of oligomers, inhibit autophagy (39, 40). As shown in this work, iron deposition led to dysfunctional autophagy and α-synuclein pathology.…”

Section: Resultsmentioning

confidence: 91%

Iron Deposition Leads to Neuronal α-Synuclein Pathology by Inducing Autophagy Dysfunction

et al. 2017

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Growing evidence has indicated that iron deposition in the substantia nigra plays an important role in Parkinson’s disease (PD). However, the underlying mechanism is still elusive. Using primary dopaminergic neurons and SH-SY5Y cells cultured in vitro, we observed that iron loading increased α-synuclein and reactive oxygen species (ROS) levels in these cells but did not affect the intracellular α-synuclein mRNA levels. Furthermore, iron loading significantly downregulated Beclin-1 levels and decreased the ratio of microtubule-associated protein 1 light chain 3 isoforms (LC3 II/LC3 I). However, a significant change in the levels of autophagy-related gene 5 (Atg5) was not observed in either neurons or SH-SY5Y cells after iron treatment. After treatment with rapamycin, the iron loading-induced increase in the α-synuclein level was significantly reversed and ROS generation was alleviated in both cultured neurons and SH-SY5Y cells. These results indicate that the inhibition of autophagy is critical for the pathological alterations in α-synuclein induced by iron loading. Moreover, treatment with vitamin E did not affect the increase in the α-synuclein levels but significantly eliminated the iron-induced ROS production. Together, our study shows that autophagy dysfunction contributes to iron-induced α-synuclein pathology.

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Proteasome inhibitor-induced autophagy in PC12 cells overexpressing A53T mutant α-synuclein

Cited by 38 publications

References 30 publications

Loss of lysosome-associated membrane protein 3 (LAMP3) enhances cellular vulnerability against proteasomal inhibition

Loss of lysosome-associated membrane protein 3 (LAMP3) enhances cellular vulnerability against proteasomal inhibition

Inhibition of Protein Ubiquitination by Paraquat and 1-Methyl-4-Phenylpyridinium Impairs Ubiquitin-Dependent Protein Degradation Pathways

Iron Deposition Leads to Neuronal α-Synuclein Pathology by Inducing Autophagy Dysfunction

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