Urate promotes SNCA/α-synuclein clearance via regulating mTOR-dependent macroautophagy

Sheng, Yulan; Chen, Xing; Hou, Xiao-Ou; Yuan, Xin; Yuan, Baoshi; Yuan, Yeqing; Zhang, Qilin; Chen, Xian; Liu, Chun‐Feng; Luo, Wei-Feng; Hu, Lifang

doi:10.1016/j.expneurol.2017.08.007

Cited by 31 publications

(19 citation statements)

References 32 publications

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“…Oxidative stress is also common autophagy inducer in cell stress [29,30]. We and others confirmed that uric acid stimulus resulted in activation of TGF-β signaling [7], down-regulation of mTOR signaling [62], and increased oxidative stress [27,28]. Thus, uric acid-induced activation of TGF-β signaling, inactivation of mTOR signaling, and increase in oxidative stress may lead to autophagy of tubular epithelial cells.…”

Section: Discussionmentioning

confidence: 67%

Pharmacological inhibition of autophagy by 3-MA attenuates hyperuricemic nephropathy

et al. 2018

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Autophagy has been identified as a cellular process of bulk degradation of cytoplasmic components and its persistent activation is critically involved in the renal damage induced by ureteral obstruction. However, the role and underlying mechanisms of autophagy in hyperuricemic nephropathy (HN) remain unknown. In the present study, we observed that inhibition of autophagy by 3-methyladenine (3-MA) abolished uric acid-induced differentiation of renal fibroblasts to myofibroblasts and activation of transforming growth factor-β1 (TGF-β1), epidermal growth factor receptor (EGFR), and Wnt signaling pathways in cultured renal interstitial fibroblasts. Treatment with 3-MA also abrogated the development of HN in vivo as evidenced by improving renal function, preserving renal tissue architecture, reducing the number of autophagic vacuoles, and decreasing microalbuminuria. Moreover, 3-MA was effective in attenuating renal deposition of extracellular matrix (ECM) proteins and expression of α-smooth muscle actin (α-SMA) and reducing renal epithelial cells arrested at the G2/M phase of cell cycle. Injury to the kidney resulted in increased expression of TGF-β1 and TGFβ receptor I, phosphorylation of Smad3 and TGF-β-activated kinase 1 (TAK1), and activation of multiple cell signaling pathways associated with renal fibrogenesis, including Wnt, Notch, EGFR, and nuclear factor-κB (NF-κB). 3-MA treatment remarkably inhibited all these responses. In addition, 3-MA effectively suppressed infiltration of macrophages and lymphocytes as well as release of multiple profibrogenic cytokines/chemokines in the injured kidney. Collectively, these findings indicate that hyperuricemia-induced autophagy is critically involved in the activation of renal fibroblasts and development of renal fibrosis and suggest that inhibition of autophagy may represent a potential therapeutic strategy for HN.

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Section: Discussionmentioning

confidence: 67%

Pharmacological inhibition of autophagy by 3-MA attenuates hyperuricemic nephropathy

et al. 2018

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“…UA also induced autophagy as demonstrated by LC3-II/LC3-I, Beclin-1 and LAMP2 increase, and a decrease in p62, which is similar to the finding that UA could induce autophagy activation via an mammalian target of rapamycin-dependent signaling in PC12 cells. 34 In human articular chondrocytes, monosodium urate crystals may also cause the death of chondrocytes through the activation of the autophagic process rather than apoptosis or ER stress. 35 In human osteoblasts, monosodium urate activate phagocytosis and NLRP3-dependent autophagy.…”

Section: Discussionmentioning

confidence: 99%

Impaired Na+−K+-ATPase signaling in renal proximal tubule contributes to hyperuricemia-induced renal tubular injury

Xiao

Zhang

et al. 2018

Exp Mol Med

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Hyperuricemia contributes to renal inflammation. We aimed to investigate the role of Na+–K+–ATPase (NKA) in hyperuricemia-induced renal tubular injury. Human primary proximal tubular epithelial cells (PTECs) were incubated with uric acid (UA) at increasing doses or for increasing lengths of time. PTECs were then stimulated by pre-incubation with an NKA α1 expression vector or small interfering RNA before UA (100 μg ml−1, 48 h) stimulation. Hyperuricemic rats were induced by gastric oxonic acid and treated with febuxostat (Feb). ATP levels, the activity of NKA and expression of its α1 subunit, Src, NOD-like receptor pyrin domain-containing protein 3 (NLRP3) and interleukin 1β (IL-1β) were measured both in vitro and in vivo. Beginning at concentrations of 100 μg ml−1, UA started to dose-dependently reduce NKA activity. UA at a concentration of 100 μg ml−1 time-dependently affected the NKA activity, with the maximal increased NKA activity at 24 h, but the activity started to decrease after 48 h. This inhibitory effect of UA on NKA activity at 48 h was in addition to a decrease in NKA α1 expression in the cell membrane, but an increase in lysosomes. This process also involved the subsequent activation of Src kinase and NLRP3, promoting IL-1β processing. In hyperuricemic rats, renal cortex NKA activity and its α1 expression were upregulated at the 7th week and both decreased at the 10th week, accompanied with increased renal cortex expression of Src, NLRP3 and IL-1β. The UA levels were reduced and renal tubular injuries in hyperuricemic rats were alleviated in the Feb group. Our data suggested that the impairment of NKA and its consequent regulation of Src, NLRP3 and IL-1β in the renal proximal tubule contributed to hyperuricemia-induced renal tubular injury.

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“…Recently, several other agents acting through an mTOR-dependent pathway have been studied in cell cultures and PD animal models. Sheng et al (2017) showed that uric acid treatment increased autophagy in PC12 cell in dose- and time-dependent manners. Moreover, uric acid reduced α-SYN accumulation in PC12 cells overexpressing wild-type or A53T mutant α-SYN.…”

Section: Description Of Cellular Proteostasis Deficits In Pdmentioning

confidence: 96%

Dysfunction of Cellular Proteostasis in Parkinson’s Disease

et al. 2019

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Despite decades of research, current therapeutic interventions for Parkinson’s disease (PD) are insufficient as they fail to modify disease progression by ameliorating the underlying pathology. Cellular proteostasis (protein homeostasis) is an essential factor in maintaining a persistent environment for neuronal activity. Proteostasis is ensured by mechanisms including regulation of protein translation, chaperone-assisted protein folding and protein degradation pathways. It is generally accepted that deficits in proteostasis are linked to various neurodegenerative diseases including PD. While the proteasome fails to degrade large protein aggregates, particularly alpha-synuclein (α-SYN) in PD, drug-induced activation of autophagy can efficiently remove aggregates and prevent degeneration of dopaminergic (DA) neurons. Therefore, maintenance of these mechanisms is essential to preserve all cellular functions relying on a correctly folded proteome. The correlations between endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) that aims to restore proteostasis within the secretory pathway are well-established. However, while mild insults increase the activity of chaperones, prolonged cell stress, or insufficient adaptive response causes cell death. Modulating the activity of molecular chaperones, such as protein disulfide isomerase which assists refolding and contributes to the removal of unfolded proteins, and their associated pathways may offer a new approach for disease-modifying treatment. Here, we summarize some of the key concepts and emerging ideas on the relation of protein aggregation and imbalanced proteostasis with an emphasis on PD as our area of main expertise. Furthermore, we discuss recent insights into the strategies for reducing the toxic effects of protein unfolding in PD by targeting the ER UPR pathway.

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Urate promotes SNCA/α-synuclein clearance via regulating mTOR-dependent macroautophagy

Cited by 31 publications

References 32 publications

Pharmacological inhibition of autophagy by 3-MA attenuates hyperuricemic nephropathy

Pharmacological inhibition of autophagy by 3-MA attenuates hyperuricemic nephropathy

Impaired Na+−K+-ATPase signaling in renal proximal tubule contributes to hyperuricemia-induced renal tubular injury

Dysfunction of Cellular Proteostasis in Parkinson’s Disease

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