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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.
- Source :
-
Toxicology & Applied Pharmacology . Feb2022, Vol. 436, pN.PAG-N.PAG. 1p. - Publication Year :
- 2022
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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. • PDE4 inhibition by roflupram attenuated cellular apoptosis in the α-syn A53T model • Roflupram inhibited the phosphorylation of Parkin and p38 MAPK • Roflupram decreased the interaction between p38 MAPK and Parkin • Roflupram promoted the mitochondrial translocation of Parkin • The protective effects of roflupram were mediated in a PKA-dependent way [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 0041008X
- Volume :
- 436
- Database :
- Academic Search Index
- Journal :
- Toxicology & Applied Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 154819859
- Full Text :
- https://doi.org/10.1016/j.taap.2021.115859