Synergistic neuroprotection by coffee components eicosanoyl-5-hydroxytryptamide and caffeine in models of Parkinson's disease and DLB

Yan, Run‐Tao; Zhang, Jie; Park, Hye-Jin; Park, Eun Su; Oh, Stephanie E.; Zheng, Haiyan; Junn, Eunsung; Voronkov, Michael V.; Stock, Jeffry B.; Mouradian, M. Maral

doi:10.1073/pnas.1813365115

Cited by 63 publications

(52 citation statements)

References 64 publications

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“…In a human α-syn transgenic mouse model, using an EHT-enhanced diet, S129 phosphorylation was decreased, with concomitant reduction in α-syn aggregation and improvement of neuronal integrity leading to improved motor performance. Equivalent results were obtained on a similar WT α-syn transgenic mouse model, showing a synergistic effect of caffeine and EHT in enhancing PP2A activation [133]. These mechanisms of enhancing PP2A dephosphorylation of α-syn appear as promising therapeutic approaches, as they are safe and can be specific to α-syn through an allosteric activation, therefore avoiding the deleterious effects towards off-target proteins.…”

Section: Phosphorylationmentioning

confidence: 83%

“…Given the colocalization of α-syn with the lysosomal marker cathepsin D, the immunized mice could activate degradation pathways and thus eliminate α-syn more efficiently [203]. Following this study, another vaccination approach fused α-syn epitopes (α-syn [85][86][87][88][89][90][91][92][93][94][95][96][97][98][99] , α-syn [109][110][111][112][113][114][115][116][117][118][119][120][121][122][123][124][125][126] , α-syn [126][127][128][129][130][131][132][133][134][135][136][137][138][139]…”

Section: Active Immunizationmentioning

confidence: 99%

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Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

et al. 2020

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Parkinson’s Disease (PD) is characterized both by the loss of dopaminergic neurons in the substantia nigra and the presence of cytoplasmic inclusions called Lewy Bodies. These Lewy Bodies contain the aggregated α-synuclein (α-syn) protein, which has been shown to be able to propagate from cell to cell and throughout different regions in the brain. Due to its central role in the pathology and the lack of a curative treatment for PD, an increasing number of studies have aimed at targeting this protein for therapeutics. Here, we reviewed and discussed the many different approaches that have been studied to inhibit α-syn accumulation via direct and indirect targeting. These analyses have led to the generation of multiple clinical trials that are either completed or currently active. These clinical trials and the current preclinical studies must still face obstacles ahead, but give hope of finding a therapy for PD with time.

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Section: Phosphorylationmentioning

confidence: 83%

Section: Active Immunizationmentioning

confidence: 99%

Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

et al. 2020

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“…The cytoprotective effect of Synucleozid was tested against α-synuclein PFFs. Human α-synuclein was expressed (79) and fibrillization was induced as previously described (80). SH-SY5Y cells were pretreated with Synucleozid (0.25 to 1 μM) for 24 h and challenged with 50 μg/mL α-synuclein PFFs for an additional 48 h in the presence of Synucleozid.…”

Section: Methodsmentioning

confidence: 99%

Translation of the intrinsically disordered protein α-synuclein is inhibited by a small molecule targeting its structured mRNA

Zhang

Park

Zhang

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Many proteins are refractory to targeting because they lack small-molecule binding pockets. An alternative to drugging these proteins directly is to target the messenger (m)RNA that encodes them, thereby reducing protein levels. We describe such an approach for the difficult-to-target protein α-synuclein encoded by the SNCA gene. Multiplication of the SNCA gene locus causes dominantly inherited Parkinson’s disease (PD), and α-synuclein protein aggregates in Lewy bodies and Lewy neurites in sporadic PD. Thus, reducing the expression of α-synuclein protein is expected to have therapeutic value. Fortuitously, the SNCA mRNA has a structured iron-responsive element (IRE) in its 5′ untranslated region (5′ UTR) that controls its translation. Using sequence-based design, we discovered small molecules that target the IRE structure and inhibit SNCA translation in cells, the most potent of which is named Synucleozid. Both in vitro and cellular profiling studies showed Synucleozid directly targets the α-synuclein mRNA 5′ UTR at the designed site. Mechanistic studies revealed that Synucleozid reduces α-synuclein protein levels by decreasing the amount of SNCA mRNA loaded into polysomes, mechanistically providing a cytoprotective effect in cells. Proteome- and transcriptome-wide studies showed that the compound’s selectivity makes Synucleozid suitable for further development. Importantly, transcriptome-wide analysis of mRNAs that encode intrinsically disordered proteins revealed that each has structured regions that could be targeted with small molecules. These findings demonstrate the potential for targeting undruggable proteins at the level of their coding mRNAs. This approach, as applied to SNCA, is a promising disease-modifying therapeutic strategy for PD and other α-synucleinopathies.

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“…For instance, recent studies have described a positive association between caffeine ingestion and improvement of exercise performance (Grgic et al, 2019) and a new mode of action of this compound at the mitochondrial level with beneficial effects on cardiovascular diseases (Ale-Agha et al, 2018). In addition to the potential role of caffeine as a protective agent on Parkinson's disease, Yan et al (2018) showed that the co-administration with eicosanoyl-5-hydroxytryptamide (another compound purified from coffee) enhanced the activity of a specific phosphatase that acts on α-synuclein, a characteristic pathogenic protein. However, another study (with more than 340,000 individuals) showed that those who consumed more than 6 cups of coffee a day had 22% more chances of developing cardiovascular diseases than nondrinkers (11%) and drinkers of decaffeinated coffee (7%) (Zhou and Hyppönen, 2019).…”

Section: Introductionmentioning

confidence: 99%

What is in a “Cup of Joe”? From green beans to spent grounds: a mini-review on coffee composition and health benefits

Celli¹,

Camargo²

2019

JFB

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Coffee is one of the most popular beverages consumed worldwide and is amongst the main dietary sources of bioactive compounds. Recent studies have described a positive association between caffeine ingestion and health, including improvement of exercise performance and enhancement of long-term memories in humans. However, from roasting to extraction, the processing of the coffee beans has a significant impact on the profile of bioactive compounds. For instance, roasting results on the reduction of 5-caffeoylquinic acid and trigonelline, while increases the concentration of melanoidins. Another important component is its lipid fraction (known as coffee oil), which can migrate to the surface of the beans and undergo changes in its composition during roasting. This mini-review presents an overview of the composition of coffee, including changes that occur during processing-from green beans to spent grounds, and recent research on its health benefits, with special focus on their antioxidant properties.

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Synergistic neuroprotection by coffee components eicosanoyl-5-hydroxytryptamide and caffeine in models of Parkinson's disease and DLB

Cited by 63 publications

References 64 publications

Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

Translation of the intrinsically disordered protein α-synuclein is inhibited by a small molecule targeting its structured mRNA

What is in a “Cup of Joe”? From green beans to spent grounds: a mini-review on coffee composition and health benefits

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