Small Molecule Fisetin Modulates Alpha–Synuclein Aggregation

Phenolic compounds are thought to be important to prevent neurodegenerative diseases (ND). Parkinson’s Disease (PD) is a neurodegenerative disorder known for its typical motor features, the deposition of α-synuclein (αsyn)-positive inclusions in the brain, and for concomitant cellular pathologies that include oxidative stress and neuroinflammation. Neuroprotective activity of fisetin, a dietary flavonoid, was evaluated against main hallmarks of PD in relevant cellular models. At physiologically relevant concentrations, fisetin protected SH-SY5Y cells against oxidative stress overtaken by tert-butyl hydroperoxide (t-BHP) and against methyl-4-phenylpyridinuim (MPP+)-induced toxicity in dopaminergic neurons, the differentiated Lund human Mesencephalic (LUHMES) cells. In this cellular model, fisetin promotes the increase of the levels of dopamine transporter. Remarkably, fisetin reduced the percentage of cells containing αsyn inclusions as well as their size and subcellular localization in a yeast model of αsyn aggregation. Overall, our data show that fisetin exerts modulatory activities toward common cellular pathologies present in PD; remarkably, it modulates αsyn aggregation, supporting the idea that diets rich in this compound may prove beneficial.

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Effect of Nebivolol on MPTP Induced Parkinson’s Disease in Mice

International Journal of Pharmaceutical Sciences Review and Research ◽

10.47583/ijpsrr.2021.v69i01.020 ◽

2021 ◽

Vol 69 (1) ◽

Author(s):

Karthigadevi. K ◽

Anbazhagan. S ◽

Jajjara Gopi Sudheer Kumar ◽

Kavimani. S

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Parkinson Disease ◽

Dopaminergic Neurons ◽

Neurodegenerative Disorder ◽

Blocking Agent ◽

Protective Effects ◽

The Brain ◽

Anti Inflammation

Parkinson’s disease is the major neurodegenerative disorder, which is due to the loss of dopaminergic neurons in the brain and results in bradykinesia, rigidity, tremor and instable posture. Oxidative stress, Inflammation, Apoptosis has been implicated in the molecular etiopathogenesis of Parkinson disease. In the present study, Nebivolol, a Cardioselective ?-blocking agent which is also reported as an antioxidant, anti-inflammation, anticonvulsant, inhibition of apoptosis and protective effects on gastric ulcer. Hence, nebivolol has been tested for its antiparkinson activity against 1-Methyl, 4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP) induced model of Parkinson disease in mice. From this study, the result shown that the nebivolol exerts its beneficial effect against MPTP induced Parkinson’s disease by virtue of its antioxidative, anti-inflammatory and by increases the Dopamine levels in the brain.

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Lycopodium Attenuates Loss of Dopaminergic Neurons by Suppressing Oxidative Stress and Neuroinflammation in a Rat Model of Parkinson’s Disease

Molecules ◽

10.3390/molecules24112182 ◽

2019 ◽

Vol 24 (11) ◽

pp. 2182 ◽

Cited By ~ 8

Author(s):

Richard L. Jayaraj ◽

Rami Beiram ◽

Sheikh Azimullah ◽

Mohamed Fizur Nagoor Meeran ◽

Shreesh K. Ojha ◽

...

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Rat Model ◽

Dopaminergic Neurons ◽

Neurodegenerative Disorder ◽

Alpha Synuclein ◽

Stress Factors ◽

Definitive Treatment ◽

And Oxidative Stress

Parkinson’s disease, a chronic, age related neurodegenerative disorder, is characterized by a progressive loss of nigrostriatal dopaminergic neurons. Several studies have proven that the activation of glial cells, presence of alpha-synuclein aggregates, and oxidative stress, fuels neurodegeneration, and currently there is no definitive treatment for PD. In this study, a rotenone-induced rat model of PD was used to understand the neuroprotective potential of Lycopodium (Lyc), a commonly-used potent herbal medicine. Immunohistochemcial data showed that rotenone injections significantly increased the loss of dopaminergic neurons in the substantia nigra, and decreased the striatal expression of tyrosine hydroxylase. Further, rotenone administration activated microglia and astroglia, which in turn upregulated the expression of α-synuclein, pro-inflammatory, and oxidative stress factors, resulting in PD pathology. However, rotenone-injected rats that were orally treated with lycopodium (50 mg/kg) were protected against dopaminergic neuronal loss by diminishing the expression of matrix metalloproteinase-3 (MMP-3) and MMP-9, as well as reduced activation of microglia and astrocytes. This neuroprotective mechanism not only involves reduction in pro-inflammatory response and α-synuclein expression, but also synergistically enhanced antioxidant defense system by virtue of the drug’s multimodal action. These findings suggest that Lyc has the potential to be further developed as a therapeutic candidate for PD.

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Alpha-Synuclein Aggregation in Parkinson's Disease

Frontiers in Medicine ◽

10.3389/fmed.2021.736978 ◽

2021 ◽

Vol 8 ◽

Author(s):

E. Srinivasan ◽

G. Chandrasekhar ◽

P. Chandrasekar ◽

K. Anbarasu ◽

A. S. Vickram ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopaminergic Neurons ◽

Genetic Factors ◽

Neurodegenerative Disorder ◽

Neuronal Loss ◽

Alpha Synuclein ◽

Substantia Nigra Pars Compacta ◽

Vulnerability Factors ◽

Alpha Synuclein Aggregation

Parkinson's disease (PD), a neurodegenerative disorder characterized by distinct aging-independent loss of dopaminergic neurons in substantia nigra pars compacta (SNpc) region urging toward neuronal loss. Over the decade, various key findings from clinical perspective to molecular pathogenesis have aided in understanding the genetics with assorted genes related with PD. Subsequently, several pathways have been incriminated in the pathogenesis of PD, involving mitochondrial dysfunction, protein aggregation, and misfolding. On the other hand, the sporadic form of PD cases is found with no genetic linkage, which still remain an unanswered question? The exertion in ascertaining vulnerability factors in PD considering the genetic factors are to be further dissevered in the forthcoming decades with advancement in research studies. One of the major proponents behind the prognosis of PD is the pathogenic transmutation of aberrant alpha-synuclein protein into amyloid fibrillar structures, which actuates neurodegeneration. Alpha-synuclein, transcribed by SNCA gene is a neuroprotein found predominantly in brain. It is implicated in the modulation of synaptic vesicle transport and eventual release of neurotransmitters. Due to genetic mutations and other elusive factors, the alpha-synuclein misfolds into its amyloid form. Therefore, this review aims in briefing the molecular understanding of the alpha-synuclein associated with PD.

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Synergistic Effects of Milk-Derived Exosomes and Galactose on α-Synuclein Pathology in Parkinson’s Disease and Type 2 Diabetes Mellitus

International Journal of Molecular Sciences ◽

10.3390/ijms22031059 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1059

Author(s):

Bodo C. Melnik

Keyword(s):

Oxidative Stress ◽

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Dopaminergic Neurons ◽

Vagal Nerve ◽

Β Cells ◽

Pancreatic Β Cells ◽

The Brain

Epidemiological studies associate milk consumption with an increased risk of Parkinson’s disease (PD) and type 2 diabetes mellitus (T2D). PD is an α-synucleinopathy associated with mitochondrial dysfunction, oxidative stress, deficient lysosomal clearance of α-synuclein (α-syn) and aggregation of misfolded α-syn. In T2D, α-syn promotes co-aggregation with islet amyloid polypeptide in pancreatic β-cells. Prion-like vagal nerve-mediated propagation of exosomal α-syn from the gut to the brain and pancreatic islets apparently link both pathologies. Exosomes are critical transmitters of α-syn from cell to cell especially under conditions of compromised autophagy. This review provides translational evidence that milk exosomes (MEX) disturb α-syn homeostasis. MEX are taken up by intestinal epithelial cells and accumulate in the brain after oral administration to mice. The potential uptake of MEX miRNA-148a and miRNA-21 by enteroendocrine cells in the gut, dopaminergic neurons in substantia nigra and pancreatic β-cells may enhance miRNA-148a/DNMT1-dependent overexpression of α-syn and impair miRNA-148a/PPARGC1A- and miRNA-21/LAMP2A-dependent autophagy driving both diseases. MiRNA-148a- and galactose-induced mitochondrial oxidative stress activate c-Abl-mediated aggregation of α-syn which is exported by exosome release. Via the vagal nerve and/or systemic exosomes, toxic α-syn may spread to dopaminergic neurons and pancreatic β-cells linking the pathogenesis of PD and T2D.

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Are lysosomes potential therapeutic targets for Parkinson’s disease?

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527320666210809123630 ◽

2021 ◽

Vol 20 ◽

Author(s):

A. Petese ◽

V. Cesaroni ◽

S. Cerri ◽

F. Blandini

Keyword(s):

Neurodegenerative Disorder ◽

Association Studies ◽

Lewy Bodies ◽

Alpha Synuclein ◽

Genome Wide Association Studies ◽

Lysosomal Dysfunction ◽

Genome Wide ◽

Nigrostriatal Neurons ◽

Disease Modifying Treatment ◽

Alpha Synuclein Aggregation

Background: Parkinson´s disease (PD) is the second most common neurodegenerative disorder, affecting 2-3% of the population over 65 years old. In addition to progressive degeneration of nigrostriatal neurons, the histopathological feature of PD is the accumulation of misfolded α-synuclein protein in abnormal cytoplasmatic inclusions, known as Lewy bodies (LBs). Recently, genome-wide association studies (GWAS) have indicated a clear association of variants within several lysosomal genes with risk for PD. Newly evolving data have been shedding light on the relationship between lysosomal dysfunction and alpha-synuclein aggregation. Defects in lysosomal enzymes could lead to the insufficient clearance of neurotoxic protein materials, possibly leading to selective degeneration of dopaminergic neurons. Specific modulation of lysosomal pathways and their components could be considered a novel opportunity for therapeutic intervention for PD. Aim: The purpose of this review is to illustrate lysosomal biology and describe the role of lysosomal dysfunction in PD pathogenesis. Finally, the most promising novel therapeutic approaches designed to modulate lysosomal activity, as a potential disease-modifying treatment for PD will be highlighted.

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Parkinson's Disease

Advances in Medical Diagnosis, Treatment, and Care - Handbook of Research on Critical Examinations of Neurodegenerative Disorders ◽

10.4018/978-1-5225-5282-6.ch012 ◽

2019 ◽

pp. 252-273 ◽

Cited By ~ 1

Author(s):

Vaibhav Walia ◽

Ashish Gakkhar ◽

Munish Garg

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Dopaminergic Neurons ◽

Older Patients ◽

Neurodegenerative Disorder ◽

Progressive Loss ◽

The Brain

Parkinson's disease (PD) is a neurodegenerative disorder in which a progressive loss of the dopaminergic neurons occurs. The loss of the neurons is most prominent in the substantia nigra region of the brain. The prevalence of PD is much greater among the older patients suggesting the risk of PD increases with the increase of age. The exact cause of the neurodegeneration in PD is not known. In this chapter, the authors introduce PD, demonstrate its history, pathogenesis, neurobiology, sign and symptoms, diagnosis, and pharmacotherapy.

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Oxidative Stress Partially Contributes to Iron-Induced Alpha-Synuclein Aggregation in SK-N-SH Cells

Neurotoxicity Research ◽

10.1007/s12640-010-9187-x ◽

2010 ◽

Vol 19 (3) ◽

pp. 435-442 ◽

Cited By ~ 36

Author(s):

Wenjing Li ◽

Hong Jiang ◽

Ning Song ◽

Junxia Xie

Keyword(s):

Oxidative Stress ◽

Alpha Synuclein ◽

Alpha Synuclein Aggregation

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Effect of Curcumin on Lifespan, Activity Pattern, Oxidative Stress, and Apoptosis in the Brains of TransgenicDrosophilaModel of Parkinson’s Disease

BioMed Research International ◽

10.1155/2014/606928 ◽

2014 ◽

Vol 2014 ◽

pp. 1-6 ◽

Cited By ~ 35

Author(s):

Yasir Hasan Siddique ◽

Falaq Naz ◽

Smita Jyoti

Keyword(s):

Oxidative Stress ◽

Activity Pattern ◽

Dopaminergic Neurons ◽

Protein Carbonyl ◽

Alpha Synuclein ◽

Significant Delay ◽

Protein Carbonyl Content ◽

Activity Monitors ◽

Intracellular Aggregates ◽

Dose Dependent

Background. A time dependent loss of dopaminergic neurons and the formation of intracellular aggregates of alpha synuclein have been reported in PD model flies.Methods. The progeny (PD flies) expressing human alpha synuclein was exposed to 25, 50, and 100 µM of curcumin mixed in the diet for 24 days. The effect of curcumin was studied on lifespan, activity pattern, oxidative stress, and apoptosis in the brains of PD model flies. The activity of PD model flies was monitored by usingDrosophilaactivity monitors (DAMs). For the estimation of oxidative stress, lipid peroxidation and protein carbonyl content were estimated in the flies brains of each treated groups. The cell death inDrosophilabrain was analyzed by isolating brains in Ringer’s solution placing them in 70% ethanol and stained in acridine orange to calculate the gray scale values.Results. The exposure of flies to 25, 50, and 100 µM of curcumin showed a dose dependent significant delay in the loss of activity pattern, reduction in the oxidative stress and apoptosis, and increase in the life span of PD model flies.Conclusion. Curcumin is potent in reducing PD symptoms.

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Blood Plasma of Patients with Parkinson’s Disease Increases Alpha-Synuclein Aggregation and Neurotoxicity

Parkinson s Disease ◽

10.1155/2016/7596482 ◽

2016 ◽

Vol 2016 ◽

pp. 1-14 ◽

Cited By ~ 2

Author(s):

Peng Wang ◽

Xin Li ◽

Xuran Li ◽

Weiwei Yang ◽

Shun Yu

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Alternative Pathway ◽

Lewy Bodies ◽

Normal Subjects ◽

Alpha Synuclein ◽

Phosphatase 2A ◽

Alpha Synuclein Aggregation ◽

The Brain ◽

Neighboring Neuron

A pathological hallmark of Parkinson’s disease (PD) is formation of Lewy bodies in neurons of the brain. This has been attributed to the spread of α-synuclein (α-syn) aggregates, which involves release of α-syn from a neuron and its reuptake by a neighboring neuron. We found that treatment with plasma from PD patients induced more α-syn phosphorylation and oligomerization than plasma from normal subjects (NS). Compared with NS plasma, PD plasma added to primary neuron cultures caused more cell death in the presence of extracellular α-syn. This was supported by the observations that phosphorylated α-syn oligomers entered neurons, rapidly increased accumulated thioflavin S-positive inclusions, and induced a series of metabolic changes that included activation of polo-like kinase 2, inhibition of glucocerebrosidase and protein phosphatase 2A, and reduction of ceramide levels, all of which have been shown to promote α-syn phosphorylation and aggregation. We also analyzed neurotoxicity of α-syn oligomers relative to plasma from different patients. Neurotoxicity was not related to age or gender of the patients. However, neurotoxicity was positively correlated with H&Y staging score. The modification in the plasma may promote spreading of α-syn aggregates via an alternative pathway and accelerate progression of PD.

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Association Between Decreased Srpk3 Expression And An Increase In Substantia Nigra Alpha-Synuclein Levels In An MPTP-Induced Parkinson’s Disease Mouse Model

10.21203/rs.3.rs-1207279/v1 ◽

2022 ◽

Author(s):

Min Hyung Seo ◽

Sujung Yeo

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Dopaminergic Neurons ◽

Cell Loss ◽

Alpha Synuclein ◽

Mice Model ◽

Dopaminergic Cell ◽

The Brain

Abstract Parkinson’s disease (PD) is known as the second most common neurodegenerative disease, which is caused by destruction of dopaminergic neurons in the substantia nigra (SN) of the brain; however, the reason for the death of dopaminergic neurons remains unclear. An increase in α-synuclein (α-syn) is considered an important factor in the pathogenesis of PD. In the current study, we investigated the association between PD and serine/arginine-rich protein specific kinase 3 (Srpk3) in MPTP-induced parkinsonism mice model and in SH-SY5Y cells treated with MPP+. Srpk3 expression was significantly downregulated, while tyrosine hydroxylase (TH) decreased and α-synuclein (α-syn) increased after 4 weeks of MPTP intoxication treatment. Dopaminergic cell reduction and α-syn increase were demonstrated by inhibiting Srpk3 expression by siRNA in SH-SY5Y cells. Moreover, a decrease in Srpk3 expression upon siRNA treatment promoted dopaminergic cell reduction and α-syn increase in SH-SY5Y cells treated with MPP+. These results suggest that the decrease in Srpk3 expression due to Srpk3 siRNA caused both a decrease in TH and an increase in α-syn. This raises new possibilities for studying how Srpk3 controls dopaminergic cells and α-syn expression, which may be related to the pathogenesis of PD. Our results provide an avenue for understanding the role of Srpk3 during dopaminergic cell loss and α-syn increase in the SN. Furthermore, this study could support a therapeutic possibility for PD in that the maintenance of Srpk3 expression inhibited dopaminergic cell reduction.

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