کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1983405 1539869 2016 11 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
The novel mechanism of rotenone-induced α-synuclein phosphorylation via reduced protein phosphatase 2A activity
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی زیست شیمی
پیش نمایش صفحه اول مقاله
The novel mechanism of rotenone-induced α-synuclein phosphorylation via reduced protein phosphatase 2A activity
چکیده انگلیسی


• PP2A plays a critical role in the rotenone-induced abnormal phosphorylation of α-syn.
• Calmodulin–SRC–PP2A pathway might be involved in the rotenone reduced PP2A activity.
• This study may provide a new treatment strategy for PD based on PP2A.

Rotenone has been shown to induce many parkinsonian features and has been widely used in chemical models of Parkinson’s disease (PD). Its use is closely associated with α-synuclein (α-syn) phosphorylation both in vivo and in vitro. However, the mechanisms whereby rotenone regulates α-syn phosphorylation remain unknown. Protein phosphatase 2A (PP2A) has been shown to play an important role in α-syn dephosphorylation. We therefore investigated if rotenone caused α-syn phosphorylation by down-regulation of PP2A activity in mice. Rotenone increased the phosphorylation of α-syn at Ser129, consistent with the inhibition of PP2A activity by increased phosphorylation of tyrosine 307 at the catalytic subunit of PP2A (pTyr307 PP2Ac). We further explored the interactions among rotenone, PP2A, and α-syn in SK-N-SH cells and primary rat cortical neurons. Rotenone inhibited PP2A activity via phosphorylation of PP2Ac at Tyr307. The reduction in PP2A activity and rotenone cytotoxicity were reversed by treatment with the PP2A agonist, C2 ceramide, and the Src kinase inhibitor, SKI606. Immunoprecipitation experiments showed that rotenone induced an increase in calmodulin–Src complex in SK-N-SH cells, thus activating Src kinase, which in turn phosphorylated PP2A at Tyr307 and inhibited its activity. C2 ceramide and SKI606 significantly reversed the rotenone-induced phosphorylation and aggregation of α-syn by increasing PP2A activity. These results demonstrate that rotenone-reduced PP2A activity via Src kinase is involved in the phosphorylation of α-syn. These findings clarify the novel mechanisms whereby rotenone can induce PD.

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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: The International Journal of Biochemistry & Cell Biology - Volume 75, June 2016, Pages 34–44
نویسندگان
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