Kaemperfol Protects Dopaminergic Neurons by Promoting mTOR-Mediated Autophagy in Parkinson's Disease Models.
Neurochemical research
We previously showed that kaempferol (KAE) could exert neuroprotective effects against PD. It has been demonstrated that abnormal autophagy plays a key role in the development of PD. Mitochondrial dysfunction, involved in the development of PD, can damage dopaminergic neurons. Whether the protective effects of KAE were exerted via regulating autophagy remains largely undefined, however. This study aimed to investigate whether KAE could protect dopaminergic neurons via autophagy and the underlying mechanisms using a MPTP/MPP-stimulated PD model. Cell viability was detected by cell counting kit-8 (CCK-8) assay, and protein levels of autophagy mediators along with mTOR signaling pathway molecules were investigated by immunohistochemistry and Western blot analyses. The results showed that KAE could ameliorate the behavioral impairments of mice, reduce the loss of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra pars compacta, and reduce α-synuclein (α-syn) levels. Furthermore, KAE upregulated levels of autophagy effector protein of Beclin-1 and autophagy microtubule associated protein of light chain 3 (LC3) in the substantia nigra (SN) while rescuing mitochondrial integrity, and downregulated levels of ubiquitin binding protein p62 and cleaved caspase-3, probably by decreasing the mammalian target of rapamycin (mTOR) signaling pathway. Further in vitro experiments demonstrated similar results. In conclusion, KAE exerts neuroprotective effects against PD potentially by promoting autophagy via inhibiting the mTOR signaling pathway.
10.1007/s11064-022-03819-2
Targeting autophagy-related protein kinases for potential therapeutic purpose.
Acta pharmaceutica Sinica. B
Autophagy, defined as a scavenging process of protein aggregates and damaged organelles mediated by lysosomes, plays a significant role in the quality control of macromolecules and organelles. Since protein kinases are integral to the autophagy process, it is critically important to understand the role of kinases in autophagic regulation. At present, intervention of autophagic processes by small-molecule modulators targeting specific kinases has becoming a reasonable and prevalent strategy for treating several varieties of human disease, especially cancer. In this review, we describe the role of some autophagy-related kinase targets and kinase-mediated phosphorylation mechanisms in autophagy regulation. We also summarize the small-molecule kinase inhibitors/activators of these targets, highlighting the opportunities of these new therapeutic agents.
10.1016/j.apsb.2019.10.003
mTOR Signaling in Parkinson's Disease.
Lan Ai-Ping,Chen Jun,Zhao Yuliang,Chai Zhifang,Hu Yi
Neuromolecular medicine
As a key regulator of cell metabolism and survival, mechanistic target of rapamycin (mTOR) emerges as a novel therapeutic target for Parkinson's disease (PD). A growing body of research indicates that restoring perturbed mTOR signaling in PD models can prevent neuronal cell death. Nevertheless, molecular mechanisms underlying mTOR-mediated effects in PD have not been fully understood yet. Here, we review recent progress in characterizing the association of mTOR signaling with PD risk factors and further discuss the potential roles of mTOR in PD.
10.1007/s12017-016-8417-7
α-synuclein suppresses microglial autophagy and promotes neurodegeneration in a mouse model of Parkinson's disease.
Tu Hai-Yue,Yuan Bao-Shi,Hou Xiao-Ou,Zhang Xiao-Jun,Pei Chong-Shuang,Ma Ya-Ting,Yang Ya-Ping,Fan Yi,Qin Zheng-Hong,Liu Chun-Feng,Hu Li-Fang
Aging cell
The cell-to-cell transfer of α-synuclein (α-Syn) greatly contributes to Parkinson's disease (PD) pathogenesis and underlies the spread of α-Syn pathology. During this process, extracellular α-Syn can activate microglia and neuroinflammation, which plays an important role in PD. However, the effect of extracellular α-Syn on microglia autophagy is poorly understood. In the present study, we reported that extracellular α-Syn inhibited the autophagy initiation, as indicated by LC3-II reduction and p62 protein elevation in BV2 and cultured primary microglia. The in vitro findings were verified in microglia-enriched population isolated from α-Syn-overexpressing mice induced by adeno-associated virus (AAV2/9)-encoded wildtype human α-Syn injection into the substantia nigra (SN). Mechanistically, α-Syn led to microglial autophagic impairment through activating toll-like receptor 4 (Tlr4) and its downstream p38 and Akt-mTOR signaling because Tlr4 knockout and inhibition of p38, Akt as well as mTOR prevented α-Syn-induced autophagy inhibition. Moreover, inhibition of Akt reversed the mTOR activation but failed to affect p38 phosphorylation triggered by α-Syn. Functionally, the in vivo evidence showed that lysozyme 2 Cre (Lyz2 )-mediated depletion of autophagy-related gene 5 (Atg5) in microglia aggravated the neuroinflammation and dopaminergic neuron losses in the SN and exacerbated the locomotor deficit in α-Syn-overexpressing mice. Taken together, the results suggest that extracellular α-Syn, via Tlr4-dependent p38 and Akt-mTOR signaling cascades, disrupts microglial autophagy activity which synergistically contributes to neuroinflammation and PD development.
10.1111/acel.13522
Neuroprotective effects of osmotin in Parkinson's disease-associated pathology via the AdipoR1/MAPK/AMPK/mTOR signaling pathways.
Journal of biomedical science
BACKGROUND:Parkinson's disease (PD) is the second most frequent age-related neurodegenerative disorder and is characterized by the loss of dopaminergic neurons. Both environmental and genetic aspects are involved in the pathogenesis of PD. Osmotin is a structural and functional homolog of adiponectin, which regulates the phosphorylation of 5' adenosine monophosphate-activated protein kinase (AMPK) via adiponectin receptor 1 (AdipoR1), thus attenuating PD-associated pathology. Therefore, the current study investigated the neuroprotective effects of osmotin using in vitro and in vivo models of PD. METHODS:The study used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced and neuron-specific enolase promoter human alpha-synuclein (NSE-hαSyn) transgenic mouse models and 1-methyl-4-phenylpyridinium (MPP)- or alpha-synuclein A53T-treated cell models. MPTP was injected at a dose of 30 mg/kg/day for five days, and osmotin was injected twice a week at a dose of 15 mg/kg for five weeks. We performed behavioral tests and analyzed the biochemical and molecular changes in the substantia nigra pars compacta (SNpc) and the striatum. RESULTS:Based on our study, osmotin mitigated MPTP- and α-synuclein-induced motor dysfunction by upregulating the nuclear receptor-related 1 protein (Nurr1) transcription factor and its downstream markers tyrosine hydroxylase (TH), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2). From a pathological perspective, osmotin ameliorated neuronal cell death and neuroinflammation by regulating the mitogen-activated protein kinase (MAPK) signaling pathway. Additionally, osmotin alleviated the accumulation of α-synuclein by promoting the AMPK/mammalian target of rapamycin (mTOR) autophagy signaling pathway. Finally, in nonmotor symptoms of PD, such as cognitive deficits, osmotin restored synaptic deficits, thereby improving cognitive impairment in MPTP- and α-synuclein-induced mice. CONCLUSIONS:Therefore, our findings indicated that osmotin significantly rescued MPTP/α-synuclein-mediated PD neuropathology. Altogether, these results suggest that osmotin has potential neuroprotective effects in PD neuropathology and may provide opportunities to develop novel therapeutic interventions for the treatment of PD.
10.1186/s12929-023-00961-z
Balancing mTOR Signaling and Autophagy in the Treatment of Parkinson's Disease.
Zhu Zhou,Yang Chuanbin,Iyaswamy Ashok,Krishnamoorthi Senthilkumar,Sreenivasmurthy Sravan Gopalkrishnashetty,Liu Jia,Wang Ziying,Tong Benjamin Chun-Kit,Song Juxian,Lu Jiahong,Cheung King-Ho,Li Min
International journal of molecular sciences
The mammalian target of rapamycin (mTOR) signaling pathway plays a critical role in regulating cell growth, proliferation, and life span. mTOR signaling is a central regulator of autophagy by modulating multiple aspects of the autophagy process, such as initiation, process, and termination through controlling the activity of the unc51-like kinase 1 (ULK1) complex and vacuolar protein sorting 34 (VPS34) complex, and the intracellular distribution of TFEB/TFE3 and proto-lysosome tubule reformation. Parkinson's disease (PD) is a serious, common neurodegenerative disease characterized by dopaminergic neuron loss in the substantia nigra pars compacta (SNpc) and the accumulation of Lewy bodies. An increasing amount of evidence indicates that mTOR and autophagy are critical for the pathogenesis of PD. In this review, we will summarize recent advances regarding the roles of mTOR and autophagy in PD pathogenesis and treatment. Further characterizing the dysregulation of mTOR pathway and the clinical translation of mTOR modulators in PD may offer exciting new avenues for future drug development.
10.3390/ijms20030728
Targeting autophagy using small-molecule compounds to improve potential therapy of Parkinson's disease.
Zhang Kai,Zhu Shiou,Li Jiamei,Jiang Tingting,Feng Lu,Pei Junping,Wang Guan,Ouyang Liang,Liu Bo
Acta pharmaceutica Sinica. B
Parkinson's disease (PD), known as one of the most universal neurodegenerative diseases, is a serious threat to the health of the elderly. The current treatment has been demonstrated to relieve symptoms, and the discovery of new small-molecule compounds has been regarded as a promising strategy. Of note, the homeostasis of the autolysosome pathway (ALP) is closely associated with PD, and impaired autophagy may cause the death of neurons and thereby accelerating the progress of PD. Thus, pharmacological targeting autophagy with small-molecule compounds has been drawn a rising attention so far. In this review, we focus on summarizing several autophagy-associated targets, such as AMPK, mTORC1, ULK1, IMPase, LRRK2, beclin-1, TFEB, GCase, ERR, C-Abelson, and as well as their relevant small-molecule compounds in PD models, which will shed light on a clue on exploiting more potential targeted small-molecule drugs tracking PD treatment in the near future.
10.1016/j.apsb.2021.02.016