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Roflupram attenuates α-synuclein-induced cytotoxicity and promotes the mitochondrial translocation of Parkin in SH-SY5Y cells overexpressing A53T mutant α-synuclein.
Toxicol Appl Pharmacol. 2022 02 01; 436:115859.TA

Abstract

We have previously shown that inhibition of cAMP-specific 3',5'-cyclic phosphodiesterase 4 (PDE4) protects against cellular toxicity in neuronal cells. Since α-synuclein (α-syn) toxicity contributes to the neurodegeneration of Parkinson's disease (PD). The aim of this study was to explore the effects and mechanisms of PDE4 on α-syn-induced neuronal toxicity. Using mutant human A53T α-syn overexpressed SH-SY5Y cells, we found that PDE4B knockdown reduced cellular apoptosis. Roflupram (ROF, 20 μM), a selective PDE4 inhibitor, produced similar protective effects and restored the morphological alterations of mitochondria. Mechanistic studies identified that α-syn enhanced the phosphorylation of Parkin at Ser131, followed by the decreased mitochondrial translocation of Parkin. Whereas both PDE4B knockdown and PDE4 inhibition by ROF blocked the effects of α-syn on Parkin phosphorylation and mitochondrial translocation. Moreover, PDE4 inhibition reversed the increase in the phosphorylation of p38 mitogen-activated protein kinase (MAPK) induced by α-syn. ROF treatment also reduced the binding of p38 MAPK to Parkin. Consistently, overexpression of PDE4B blocked the roles of ROF on p38 MAPK phosphorylation, Parkin phosphorylation, and the subsequent mitochondrial translocation of parkin. Furthermore, PDE4B overexpression attenuated the protective role of ROF, as evidenced by reduced mitochondria membrane potential and increased cellular apoptosis. Interestingly, ROF failed to suppress α-syn-induced cytotoxicity in the presence of a protein kinase A (PKA) inhibitor H-89. Our findings indicate that PDE4 facilitates α-syn-induced cytotoxicity via the PKA/p38 MAPK/Parkin pathway in SH-SY5Y cells overexpressing A53T mutant α-synuclein. PDE4 inhibition by ROF is a promising strategy for the prevention and treatment of α-syn-induced neurodegeneration.

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Authors+Show Affiliations

Zhong J
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Li M
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Xu J
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong-Macao Greater Bay Area, China; Key Laboratory of Mental Health of the Ministry of Education, Southern Medical University, Guangzhou 510515, China. Electronic address: jpx@smu.edu.cn.
Dong W
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Qin Y
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Qiu S
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Li X
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Wang H
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong-Macao Greater Bay Area, China; Key Laboratory of Mental Health of the Ministry of Education, Southern Medical University, Guangzhou 510515, China. Electronic address: wht821@smu.edu.cn.

MeSH

ApoptosisBenzene DerivativesCell Line, TumorFuransHumansMitochondriaNeuronsParkinson DiseasePhosphodiesterase 4 InhibitorsPhosphorylationUbiquitin-Protein Ligasesalpha-Synucleinp38 Mitogen-Activated Protein Kinases

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

34990728

Citation

Zhong, Jiahong, et al. "Roflupram Attenuates Α-synuclein-induced Cytotoxicity and Promotes the Mitochondrial Translocation of Parkin in SH-SY5Y Cells Overexpressing A53T Mutant Α-synuclein." Toxicology and Applied Pharmacology, vol. 436, 2022, p. 115859.
Zhong J, Li M, Xu J, et al. Roflupram attenuates α-synuclein-induced cytotoxicity and promotes the mitochondrial translocation of Parkin in SH-SY5Y cells overexpressing A53T mutant α-synuclein. Toxicol Appl Pharmacol. 2022;436:115859.
Zhong, J., Li, M., Xu, J., Dong, W., Qin, Y., Qiu, S., Li, X., & Wang, H. (2022). Roflupram attenuates α-synuclein-induced cytotoxicity and promotes the mitochondrial translocation of Parkin in SH-SY5Y cells overexpressing A53T mutant α-synuclein. Toxicology and Applied Pharmacology, 436, 115859. https://doi.org/10.1016/j.taap.2021.115859
Zhong J, et al. Roflupram Attenuates Α-synuclein-induced Cytotoxicity and Promotes the Mitochondrial Translocation of Parkin in SH-SY5Y Cells Overexpressing A53T Mutant Α-synuclein. Toxicol Appl Pharmacol. 2022 02 1;436:115859. PubMed PMID: 34990728.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Roflupram attenuates α-synuclein-induced cytotoxicity and promotes the mitochondrial translocation of Parkin in SH-SY5Y cells overexpressing A53T mutant α-synuclein. AU - Zhong,Jiahong, AU - Li,Mengfan, AU - Xu,Jiangping, AU - Dong,Wenli, AU - Qin,Yunyun, AU - Qiu,Shuqing, AU - Li,Xing, AU - Wang,Haitao, Y1 - 2022/01/04/ PY - 2021/09/08/received PY - 2021/12/08/revised PY - 2021/12/30/accepted PY - 2022/1/7/pubmed PY - 2022/2/22/medline PY - 2022/1/6/entrez KW - PDE4 KW - Parkin KW - Parkinson's Disease KW - p38 MAPK KW - α-Synuclein SP - 115859 EP - 115859 JF - Toxicology and applied pharmacology JO - Toxicol Appl Pharmacol VL - 436 N2 - We have previously shown that inhibition of cAMP-specific 3',5'-cyclic phosphodiesterase 4 (PDE4) protects against cellular toxicity in neuronal cells. Since α-synuclein (α-syn) toxicity contributes to the neurodegeneration of Parkinson's disease (PD). The aim of this study was to explore the effects and mechanisms of PDE4 on α-syn-induced neuronal toxicity. Using mutant human A53T α-syn overexpressed SH-SY5Y cells, we found that PDE4B knockdown reduced cellular apoptosis. Roflupram (ROF, 20 μM), a selective PDE4 inhibitor, produced similar protective effects and restored the morphological alterations of mitochondria. Mechanistic studies identified that α-syn enhanced the phosphorylation of Parkin at Ser131, followed by the decreased mitochondrial translocation of Parkin. Whereas both PDE4B knockdown and PDE4 inhibition by ROF blocked the effects of α-syn on Parkin phosphorylation and mitochondrial translocation. Moreover, PDE4 inhibition reversed the increase in the phosphorylation of p38 mitogen-activated protein kinase (MAPK) induced by α-syn. ROF treatment also reduced the binding of p38 MAPK to Parkin. Consistently, overexpression of PDE4B blocked the roles of ROF on p38 MAPK phosphorylation, Parkin phosphorylation, and the subsequent mitochondrial translocation of parkin. Furthermore, PDE4B overexpression attenuated the protective role of ROF, as evidenced by reduced mitochondria membrane potential and increased cellular apoptosis. Interestingly, ROF failed to suppress α-syn-induced cytotoxicity in the presence of a protein kinase A (PKA) inhibitor H-89. Our findings indicate that PDE4 facilitates α-syn-induced cytotoxicity via the PKA/p38 MAPK/Parkin pathway in SH-SY5Y cells overexpressing A53T mutant α-synuclein. PDE4 inhibition by ROF is a promising strategy for the prevention and treatment of α-syn-induced neurodegeneration. SN - 1096-0333 UR - https://www.unboundmedicine.com/medline/citation/34990728/Roflupram_attenuates_α_synuclein_induced_cytotoxicity_and_promotes_the_mitochondrial_translocation_of_Parkin_in_SH_SY5Y_cells_overexpressing_A53T_mutant_α_synuclein_ DB - PRIME DP - Unbound Medicine ER -