Curcumin Ameliorates the Neurodegenerative Pathology in A53T α-synuclein Cell Model of Parkinson’s Disease Through the Downregulation of mTOR/p70S6K Signaling and the Recovery of Macroautophagy

Abstract

Parkinson's disease (PD) is pathologically characterized by the presence of α-synuclein positive intracytoplasmic inclusions. The missense mutation, A53T α-synuclein is closely related to hereditary, early-onset PD. Accumulating evidences suggest that pathological accumulation of A53T α-synuclein protein will perturb itself to be efficiently and normally degraded through its usual degradation pathway, macroautophagy-lysosome pathway, therefore toxic effects on the neuron will be exacerbated. Based on the above fact, we demonstrated in this study that A53T α-synuclein overexpression impairs macroautophagy in SH-SY5Y cells and upregulates mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase (p70S6K) signaling, the classical suppressive pathway of autophagy. We further found that curcumin, a natural compound derived from the curry spice turmeric and with low toxicity in normal cells, could efficiently reduce the accumulation of A53T α-synuclein through downregulation of the mTOR/p70S6K signaling and recovery of macroautophagy which was suppressed. These findings suggested that the regulation of mTOR/p70S6K signaling may be a participant of the accumulation of A53T α-synuclein protein-linked Parkinsonism. Meanwhile curcumin could be a candidate neuroprotective agent by inducing macroautophagy, and needs to be further investigated by clinical application in patients suffering Parkinson's disease.

A Novel Hsp90 Inhibitor Activates Compensatory Heat Shock Protein Responses and Autophagy and Alleviates Mutant A53Tα-Synuclein Toxicity

“…Since mTOR has been reported to be a client protein of Hsp90 (Moulick et al, 2011), we hypothesized that 19-Ph-GA might modulate mTOR activity in 5Y cells overexpressing A53T a-Syn. In contrast to a recent study (Jiang et al, 2013), we observed a sustained increase in the levels of LC3 II after overexpression of either A53T or WT a-Syn in 5Y cells, whereas the concomitant induction of phosphorylated mTOR (p-mTOR) and phosphorylated p70S6K (p-p70S6K) was only detected in A53T a-Syn-overexpressing cells (Fig. 7).…”

HMGB1 is involved in autophagy inhibition caused by SNCA/α-synuclein overexpression

“…20 In contrast, SNCA A53T was shown to inhibit autophagy while WT SNCA had no obvious effect in a recent study. 26 However, the time-course changes in autophagy status had not been determined in these studies. To evaluate whether SNCA overexpression inhibits or activates autophagy, a range The levels of immunoprecipitated Becn1 were normalized to the corresponding levels of Becn1 in whole cell lysates.…”

“…These factors may contribute to the different outcomes of the previous studies. 20,26 Regardless of these factors, both WT and SNCA A53T inhibit autophagy at certain stages of overexpression. At different stages of SNCA pathology, the successive failure of protein degradation pathways (UPS, CMA, and autophagy) ultimately contributes to neuronal cell death.…”

Curcumin: Synthesis optimization andin silicointeraction with cyclin dependent kinase

“…Curcumin regulates various growth factors, protein kinases, inflammatory cytokines and transcription factors to suppress the metastases and proliferation of human tumors (4). Other than anticancer and antitumor activities, it has also shown its effects against a variety of diseases such as respiratory tract infection, hepatic steatosis, skin photoageing, Parkinson's disease, pathogenesis of obesity, diabetes, HIV-associated diarrhea and Alzheimer's disease, through inhibition of amyloid beta oligomer formation (5)(6)(7)(8). The structure-activity relationship studies of curcumin molecule against different biological targets have indicated that the presence of two phenyl rings with a C-7 linker with ketoenol function (C=O groups as hydrogen acceptors and C-4 as a hydrogen donor) are most important for its biological activities.…”