Nrf2 inducer and cncC overexpression attenuates neurodegeneration due to α-synuclein in Drosophila

2015 ◽  
Vol 93 (4) ◽  
pp. 351-358 ◽  
Author(s):  
Bing Wang ◽  
Qingqing Liu ◽  
Hongyun Shan ◽  
Chunlin Xia ◽  
Zhaohui Liu
Keyword(s):  
Signaling Pathway ◽  
Dopaminergic Neurons ◽  
Autosomal Dominant ◽  
Lewy Bodies ◽  
Antioxidant Response ◽  
Homologous Gene ◽  
Major Protein ◽  
Selective Expression ◽  
The Brain ◽  
Transgenic Flies

The study of the genes that are related to the pathogenesis of Parkinson’s disease (PD) will improve our understanding of the mechanisms that underlie the development of PD. α-Synuclein is a major protein component of Lewy bodies, which are characteristic structures of PD pathology. Mutations in α-synuclein are closely related to the early onset of autosomal dominant PD. Transgenic flies with mutant α-synuclein (A53T) display neurodegenerative changes that include movement dysfunctions and a loss of dopaminergic neurons in the brain. In the present study, we measured reactive oxygen species (ROS) levels in α-synuclein transgenic flies by monitoring the fluorescence levels of redox-sensitive indicators based on GFP (roGFP) in flies co-expressing roGFP and mutant α-synuclein. We found that the ROS levels were significantly increased in the mutant α-synuclein flies. The elevations in ROS levels were also proportionate to the behavioral disorders and the losses of dopaminergic neurons. We also found that CDDO-Me inhibited the increases in ROS levels in the A53T flies and improved the neurodegenerative changes by activating the Nrf2/antioxidant response element signaling pathway. Selective expression of the Nrf2 homologous gene cncC in the dopaminergic neurons effectively protected against the neurodegenerative phenotype of the A53T α-synuclein flies, compared to the flies that expressed cncC in all neurons. These results indicate that the reductions in oxidative stress that are mediated by the activation of the antioxidant signaling pathway can effectively attenuate the neurotoxicity caused by mutations in α-synuclein.

scholarly journals Models for LRRK2-Linked Parkinsonism

2011 ◽  
Vol 2011 ◽  
pp. 1-16 ◽  
Author(s):  
Tianxia Li ◽  
DeJun Yang ◽  
Sarah Sushchky ◽  
Zhaohui Liu ◽  
Wanli W. Smith
Keyword(s):  
Dopaminergic Neurons ◽  
Autosomal Dominant ◽  
Dopaminergic System ◽  
Late Onset ◽  
Lewy Bodies ◽  
Leucine Rich Repeat ◽  
Protein Deposition ◽  
Lrrk2 Gene ◽  
The Brain ◽  
Potential Therapeutics

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder characterized by the selective loss of dopaminergic neurons and the presence of Lewy bodies. The pathogenesis of PD is not fully understood, but it appears to involve both genetic susceptibility and environmental factors. Treatment for PD that prevents neuronal death progression in the dopaminergic system and abnormal protein deposition in the brain is not yet available. Recently, mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified to cause autosomal-dominant late-onset PD and contribute to sporadic PD. Here, we review the recent models for LRRK2-linked Parkinsonism and their utility in studying LRRK2 neurobiology, pathogenesis, and potential therapeutics.

scholarly journals Importance of Nanoparticles for the Delivery of Antiparkinsonian Drugs

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 508
Author(s):  
Sara Silva ◽  
António J. Almeida ◽  
Nuno Vale
Keyword(s):  
Side Effects ◽  
Dopaminergic Neurons ◽  
Lewy Bodies ◽  
Pharmacokinetic Profile ◽  
The Elderly ◽  
Motor Symptoms ◽  
Administration Routes ◽  
Pharmaceutical Therapy ◽  
Drug Pharmacokinetic ◽  
The Brain

Parkinson’s disease (PD) affects around ten million people worldwide and is considered the second most prevalent neurodegenerative disease after Alzheimer’s disease. In addition, there is a higher risk incidence in the elderly population. The main PD hallmarks include the loss of dopaminergic neurons and the development of Lewy bodies. Unfortunately, motor symptoms only start to appear when around 50–70% of dopaminergic neurons have already been lost. This particularly poses a huge challenge for early diagnosis and therapeutic effectiveness. Actually, pharmaceutical therapy is able to relief motor symptoms, but as the disease progresses motor complications and severe side-effects start to appear. In this review, we explore the research conducted so far in order to repurpose drugs for PD with the use of nanodelivery systems, alternative administration routes, and nanotheranostics. Overall, studies have demonstrated great potential for these nanosystems to target the brain, improve drug pharmacokinetic profile, and decrease side-effects.

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

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 391 ◽  
Author(s):  
Margaux Teil ◽  
Marie-Laure Arotcarena ◽  
Emilie Faggiani ◽  
Florent Laferriere ◽  
Erwan Bezard ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Clinical Trials ◽  
Substantia Nigra ◽  
Dopaminergic Neurons ◽  
Lewy Bodies ◽  
Curative Treatment ◽  
Preclinical Studies ◽  
Cytoplasmic Inclusions ◽  
The Many ◽  
The Brain

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.

Effect of Myricetin on the Loss of Dopaminergic Neurons in the Transgenic Drosophila Model of Parkinson’s Disease

2019 ◽  
Vol 14 (1) ◽  
pp. 58-64 ◽  
Author(s):  
Gulshan Ara ◽  
Mohammad Afzal ◽  
Smita Jyoti ◽  
Falaq Naz ◽  
Rahul ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Neuronal Damage ◽  
Radical Scavenging ◽  
Lewy Bodies ◽  
Dopamine Content ◽  
Drosophila Model ◽  
Dose Dependent ◽  
The Brain

Background: The formation of Lewy bodies is associated with the production of reactive oxygen species (ROS) and the neuronal damage specifically the dopaminergic neurons in the Parkinson’s disease patients. Hence any agent that could curtail the production of ROS /oxidative stress could act as a possible therapeutic agent thereby preventing the neuronal damage. </P><P> Method: In the present study, we first evaluated the antioxidant potential of myricetin by performing superoxide anion scavenging and diphenyl-picrylhydrazyl (DPPH) free radical scavenging assays. Myricetin at a final concentration of 10, 20 and 40&#181;M was mixed in diet and the PD flies were allowed to feed on it for 24 days. After 24 days of exposure, the dopamine content was estimated in brain and the immunohistochemistry was performed for the tyroxine hydroxylase activity on the brain sections from each group. </P><P> Results: Myricetin showed a dose-dependent increase in the antioxidative activity. The exposure of PD flies to 10, 20 and 40&#181;M of Myricetin not only showed a dose-dependent significant increase in the dopamine content compared to unexposed PD flies (p<0.05), but also prevented the loss of dopaminergic neurons in the brain of PD flies. </P><P> Conclusion: The results suggest that the antioxidative potential of myricetin is responsible for preventing the loss of dopaminergic neurons and dopamine content.

α-Synuclein in Parkinson’s Disease: Does a Prion-Like Mechanism of Propagation from Periphery to the Brain Play a Role?

2020 ◽  
pp. 107385842094318
Author(s):  
Huimin Zheng ◽  
Changhe Shi ◽  
Haiyang Luo ◽  
Liyuan Fan ◽  
Zhihua Yang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Lewy Bodies ◽  
Cellular Level ◽  
Motor Symptoms ◽  
Lewy Neurites ◽  
Growing Body ◽  
Non Motor Symptoms ◽  
The Brain

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases, defined as motor and non-motor symptoms associated with the loss of dopaminergic neurons and a decreased release of dopamine (DA). Currently, PD patients are believed to have a neuropathological basis denoted by the presence of Lewy bodies (LBs) or Lewy neurites (LNs), which mostly comprise α-synuclein (α-syn) inclusions. Remarkably, there is a growing body of evidence indicating that the inclusions undergo template-directed aggregation and propagation via template-directed among the brain and peripheral organs, mainly in a prion-like manner. Interestingly, some studies reported that an integral loop was reminiscent of the mechanism of Parkinson’s disease, denoting that α-syn as prionoid was transmitted from the periphery to the brain via specific pathways. Also the systematic life cycle of α-syn in the cellular level is illustrated. In this review, we critically assess landmark evidence in the field of Parkinson’s disease with a focus on the genesis and prion-like propagation of the α-syn pathology. The anatomical and cell-to-cell evidences are discussed to depict the theory behind the propagation and transferred pathways. Furthermore, we highlight effective therapeutic perspectives and clinical trials targeting prion-like mechanisms. Major controversies surrounding this topic are also discussed.

Comparison of Cytocidal Activities of L-DOPA and Dopamine in S. cerevisiae and C. glabrata

2020 ◽  
Vol 16 (1) ◽  
pp. 90-93
Author(s):  
Carmen E. Iriarte ◽  
Ian G. Macreadie
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Candida Glabrata ◽  
High Sensitivity ◽  
Time Dependent ◽  
Colony Forming Units ◽  
Dependent Cell ◽  
The Brain

Background: Parkinson's Disease results from a loss of dopaminergic neurons, and reduced levels of the neurotransmitter dopamine. Parkinson's Disease treatments involve increasing dopamine levels through administration of L-DOPA, which can cross the blood brain barrier and be converted to dopamine in the brain. The toxicity of dopamine has previously studied but there has been little study of L-DOPA toxicity. Methods: We have compared the toxicity of dopamine and L-DOPA in the yeasts, Saccharomyces cerevisiae and Candida glabrata by cell viability assays, measuring colony forming units. Results: L-DOPA and dopamine caused time-dependent cell killing in Candida glabrata while only dopamine caused such effects in Saccharomyces cerevisiae. The toxicity of L-DOPA is much lower than dopamine. Conclusion: Candida glabrata exhibits high sensitivity to L-DOPA and may have advantages for studying the cytotoxicity of L-DOPA.

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

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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