Irisflorentin improves α-synuclein accumulation and attenuates 6-OHDA-induced dopaminergic neuron degeneration, implication for Parkinson’s disease therapy

Chen, Yue Mi; Liu, Shih‐Ping; Lin, Hsin Lien; Chan, Ming Chia; Chen, Yen Chuan; Huang, Yü; Tsai, Min Chen; Fu, Ru Huei

doi:10.7603/s40681-015-0004-y

Cited by 27 publications

(14 citation statements)

References 29 publications

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“…Proper RPN-3 levels are critical for proteasome function as either overexpression or deletion of rpn-3 disrupted the function of the proteasome (Joshi et al 2011). Irisflorentin, an isoflavone isolated from the roots of the traditional Chinese herbal, Belamcanda chinensis , was shown to specifically upregulate rpn-3 expression, which directly increased the chymotrypsin-like activity of the proteasome (Chen et al 2015). The increased proteasome activity led to decreased alpha-synuclein accumulation and decreased toxicity in a nematode model of Parkinson’s disease.…”

Section: Resultsmentioning

confidence: 99%

Metabolome and proteome changes with aging in Caenorhabditis elegans

Copes

Edwards

Chaput

et al. 2015

Experimental Gerontology

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To expand the understanding of aging in the model organism Caenorhabditis elegans, global quantification of metabolite and protein levels in young and aged nematodes was performed using mass spectrometry. With age there was a decreased abundance of proteins functioning in transcription termination, mRNA degradation, mRNA stability, protein synthesis, and proteasomal function. Furthermore there was altered S-adenosyl methionine metabolism as well as a decreased abundance of the S-adenosyl methionine synthetase (SAMS-1) protein. Other aging-related changes included alterations in free fatty acid levels and composition, decreased levels of ribosomal proteins, decreased levels of NADP-dependent isocitrate dehydrogenase (IDH1), a shift in the cellular redox state, an increase in sorbitol content, alterations in free amino acid levels, and indications of altered muscle function and sarcoplasmic reticulum Ca2+ homeostasis. There were also decreases in pyrimidine and purine metabolite levels, most markedly nitrogenous bases. Supplementing the culture medium with cytidine (a pyrimidine nucleoside) or hypoxanthine (a purine base) increased lifespan slightly, suggesting that aging-induced alterations in ribonucleotide metabolism affect lifespan. An age-related increase in body size, lipotoxicity from ectopic yolk lipoprotein accumulation, a decline in NAD+ levels, and mitochondrial electron transport chain dysfunction may explain many of these changes. In addition, dietary restriction in aged worms resulting from sarcopenia of the pharyngeal pump likely decreases the abundance of SAMS-1, possibly leading to decreased phosphatidylcholine levels, larger lipid droplets, and ER and mitochondrial stress. The complementary use of proteomics and metabolomics yielded unique insights into the molecular processes altered with age in C. elegans.

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Section: Resultsmentioning

confidence: 99%

Metabolome and proteome changes with aging in Caenorhabditis elegans

Copes

Edwards

Chaput

et al. 2015

Experimental Gerontology

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“…The phenolic groups enhance curcumin interactions with α-syn monomers as well as oligomers. In PC12 cells transfected with recombinant plasmids, α-syn-pEGFP-A53T downregulated α-syn expression or oligomer formation by regulating apoptosis-mediated mitochondrial membrane potential (Chen et al, 2015a ). The effect of curcumin on α-syn observed in vitro was reconfirmed in vivo in genetic mouse models of synucleinopathy (Spinelli et al, 2015 ).…”

Section: Phytochemicals Targeting α-Synuclein Assembly and Toxicitymentioning

confidence: 99%

Plant Extracts and Phytochemicals Targeting α-Synuclein Aggregation in Parkinson's Disease Models

et al. 2019

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α-Synuclein (α-syn) is a presynaptic protein that regulates the release of neurotransmitters from synaptic vesicles in the brain. α-Syn aggregates, including Lewy bodies, are features of both sporadic and familial forms of Parkinson's disease (PD). These aggregates undergo several key stages of fibrillation, oligomerization, and aggregation. Therapeutic benefits of drugs decline with disease progression and offer only symptomatic treatment. Novel therapeutic strategies are required which can either prevent or delay the progression of the disease. The link between α-syn and the etiopathogenesis and progression of PD are well-established in the literature. Studies indicate that α-syn is an important therapeutic target and inhibition of α-syn aggregation, oligomerization, and fibrillation are an important disease modification strategy. However, recent studies have shown that plant extracts and phytochemicals have neuroprotective effects on α-syn oligomerization and fibrillation by targeting different key stages of its formation. Although many reviews on the antioxidant-mediated, neuroprotective effect of plant extracts and phytochemicals on PD symptoms have been well-highlighted, the antioxidant mechanisms show limited success for translation to clinical studies. The identification of specific plant extracts and phytochemicals that target α-syn aggregation will provide selective molecules to develop new drugs for PD. The present review provides an overview of plant extracts and phytochemicals that target α-syn in PD and summarizes the observed effects and the underlying mechanisms. Furthermore, we provide a synopsis of current experimental models and techniques used to evaluate plant extracts and phytochemicals. Plant extracts and phytochemicals were found to inhibit the aggregation or fibril formation of oligomers. These also appear to direct α-syn oligomer formation into its unstructured form or promote non-toxic pathways and suggested to be valuable drug candidates for PD and related synucleinopathy. Current evidences from in vitro studies require confirmation in the in vivo studies. Further studies are needed to ascertain their potential effects and safety in preclinical studies for pharmaceutical/nutritional development of these phytochemicals or dietary inclusion of the plant extracts in PD treatment.

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“…CAT-2 overexpression confers resistance to 6-OHDA in wild-type and CAT-2 mutant backgrounds possibly due to reduced 6-OHDA uptake into dopaminergic neurons when excess dopamine is present (Masoudi et al, 2014 ). Due to the conservation between mammalian and C. elegans dopamine receptors, these and other results from toxin-induced neurodegeneration studies in C. elegans may help shed light on novel mechanisms leading to dopaminergic neuroprotection (Chen Y. M. et al, 2015 ).…”

Section: Caenorhabditis Elegans Models Of Parkinson's Diseasmentioning

confidence: 99%

“…To model α-synuclein aggregation and accumulation in vivo , researchers have generated transgenic C. elegans strains that express the human α-synuclein gene in body wall muscle cells and in neurons (Table 1 ). In these models, increased or decreased fluorescence intensity associated with YFP linked to α-synuclein can be quantified to determine the levels of protein expression (Jadiya et al, 2011 ; Jadiya and Nazir, 2012 ; Fatima et al, 2014 ; Fu et al, 2014a ; Chen Y. M. et al, 2015 ; Liu et al, 2015 ). Loss of fluorescence intensity indicates reduced protein expression, whereas increased fluorescence indicates increased α-synuclein expression.…”

Section: Markers Of Pathology In Genetic and Toxin-induced Pd mentioning

confidence: 99%

Behavioral Phenotyping and Pathological Indicators of Parkinson's Disease in C. elegans Models

et al. 2017

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Parkinson's disease (PD) is a neurodegenerative disorder with symptoms that progressively worsen with age. Pathologically, PD is characterized by the aggregation of α-synuclein in cells of the substantia nigra in the brain and loss of dopaminergic neurons. This pathology is associated with impaired movement and reduced cognitive function. The etiology of PD can be attributed to a combination of environmental and genetic factors. A popular animal model, the nematode roundworm Caenorhabditis elegans, has been frequently used to study the role of genetic and environmental factors in the molecular pathology and behavioral phenotypes associated with PD. The current review summarizes cellular markers and behavioral phenotypes in transgenic and toxin-induced PD models of C. elegans.

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Irisflorentin improves α-synuclein accumulation and attenuates 6-OHDA-induced dopaminergic neuron degeneration, implication for Parkinson’s disease therapy

Cited by 27 publications

References 29 publications

Metabolome and proteome changes with aging in Caenorhabditis elegans

Metabolome and proteome changes with aging in Caenorhabditis elegans

Plant Extracts and Phytochemicals Targeting α-Synuclein Aggregation in Parkinson's Disease Models

Behavioral Phenotyping and Pathological Indicators of Parkinson's Disease in C. elegans Models

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