scholarly journals The Importance of Drosophila melanogaster Research to UnCover Cellular Pathways Underlying Parkinson’s Disease

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 579
Author(s):  
Melissa Vos ◽  
Christine Klein
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Drosophila Melanogaster ◽  
Neurodegenerative Disorder ◽  
Symptomatic Treatment ◽  
Good Alternative ◽  
Disease Genes ◽  
Disease Etiology ◽  
Underlying Mechanisms ◽  
Disease Pathways

Parkinson’s disease (PD) is a complex neurodegenerative disorder that is currently incurable. As a consequence of an incomplete understanding of the etiology of the disease, therapeutic strategies mainly focus on symptomatic treatment. Even though the majority of PD cases remain idiopathic (~90%), several genes have been identified to be causative for PD, facilitating the generation of animal models that are a good alternative to study disease pathways and to increase our understanding of the underlying mechanisms of PD. Drosophila melanogaster has proven to be an excellent model in these studies. In this review, we will discuss the different PD models in flies and key findings identified in flies in different affected pathways in PD. Several molecular changes have been identified, of which mitochondrial dysfunction and a defective endo-lysosomal pathway emerge to be the most relevant for PD pathogenesis. Studies in flies have significantly contributed to our knowledge of how disease genes affect and interact in these pathways enabling a better understanding of the disease etiology and providing possible therapeutic targets for the treatment of PD, some of which have already resulted in clinical trials.

scholarly journals Nicotinamide mononucleotide treatment increases NAD+ levels in an iPSC Model of Parkinson’s Disease but does not impact sirtuin activity

2020 ◽  
Author(s):  
Brett Fulleylove-Krause ◽  
Samantha Sison ◽  
Allison Ebert
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Stem Cell ◽  
Dopaminergic Neurons ◽  
Neurodegenerative Disorder ◽  
Nicotinamide Mononucleotide ◽  
Reduce Activity ◽  
Underlying Mechanisms ◽  
Reduced Nicotinamide Adenine Dinucleotide ◽  
Dopaminergic Neuron Loss

Abstract Objectives: Parkinson’s disease (PD) is a common neurodegenerative disorder caused by the loss of dopaminergic neurons in the substantia nigra. Although the underlying mechanisms of dopaminergic neuron loss is not fully understood, evidence suggests mitochondrial malfunction as a key contributor to disease pathogenesis. We previously found that human PD patient stem cell-derived dopaminergic neurons exhibit reduced nicotinamide adenine dinucleotide (NAD+) levels and reduce activity of sirtuins, a group of NAD+-dependent deacetylase enzymes that participate in the regulation of mitochondrial function, energy production, and cell survival. Thus, here we tested whether treatment of PD stem cell-derived dopaminergic neurons with nicotinamide mononucleotide (NMN), an NAD+ precursor, could increase NAD+ levels and improve sirtuin activity. Results: We treated PD iPSC-derived dopaminergic neurons with NMN and found that NAD+ levels did increase. The deacetylase activity of sirtuin (SIRT) 2 was improved with NMN treatment, but NMN had no impact on deacetylase activity of SIRT 1 or 3. These results suggest that NMN can restore NAD+ levels and SIRT 2 activity, but that additional mechanisms are involved SIRT 1 and 3 dysregulation in PD dopaminergic neurons.

scholarly journals Single-cell transcriptomics of human iPSC differentiation dynamics reveal a core molecular network of Parkinson’s disease

2022 ◽  
Vol 5 (1) ◽  
Author(s):  
Gabriela Novak ◽  
Dimitrios Kyriakis ◽  
Kamil Grzyb ◽  
Michela Bernini ◽  
Sophie Rodius ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Single Cell ◽  
Neurodegenerative Disorder ◽  
Control Cell ◽  
Dopamine Metabolism ◽  
Core Network ◽  
Protein Coding ◽  
Disease Associated Genes ◽  
Underlying Mechanisms

AbstractParkinson’s disease (PD) is the second-most prevalent neurodegenerative disorder, characterized by the loss of dopaminergic neurons (mDA) in the midbrain. The underlying mechanisms are only partly understood and there is no treatment to reverse PD progression. Here, we investigated the disease mechanism using mDA neurons differentiated from human induced pluripotent stem cells (hiPSCs) carrying the ILE368ASN mutation within the PINK1 gene, which is strongly associated with PD. Single-cell RNA sequencing (RNAseq) and gene expression analysis of a PINK1-ILE368ASN and a control cell line identified genes differentially expressed during mDA neuron differentiation. Network analysis revealed that these genes form a core network, members of which interact with all known 19 protein-coding Parkinson’s disease-associated genes. This core network encompasses key PD-associated pathways, including ubiquitination, mitochondrial function, protein processing, RNA metabolism, and vesicular transport. Proteomics analysis showed a consistent alteration in proteins of dopamine metabolism, indicating a defect of dopaminergic metabolism in PINK1-ILE368ASN neurons. Our findings suggest the existence of a network onto which pathways associated with PD pathology converge, and offers an inclusive interpretation of the phenotypic heterogeneity of PD.

scholarly journals Pesticides and Parkinson’s Disease

2001 ◽  
Vol 1 ◽  
pp. 207-208 ◽  
Author(s):  
Todd B. Sherer ◽  
Ranjita Betarbet ◽  
J. Timothy Greenamyre
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Lewy Bodies ◽  
Substantia Nigra Pars Compacta ◽  
Selective Death ◽  
Underlying Mechanisms ◽  
Common Neurodegenerative Disorder

Parkinson’s disease (PD), a common neurodegenerative disorder affects approximately 1% of the population over 65. PD is a late-onset progressive motor disease characterized by tremor, rigidity (stiffness), and bradykinesia (slowness of movement). The hallmark of PD is the selective death of dopamine-containing neurons in the substantia nigra pars compacta which send their projections to the striatum and the presence of cytoplasmic aggregates called Lewy bodies [1-2]. Most cases of PD are sporadic but rare cases are familial, with earlier onset. The underlying mechanisms and causes of PD still remain unclear.

scholarly journals Treatment of Parkinson's Disease

2003 ◽  
Vol 30 (S1) ◽  
pp. S27-S33 ◽  
Author(s):  
W.R. Wayne Martin ◽  
Marguerite Wieler
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Functional Disability ◽  
Neurodegenerative Disorder ◽  
Holistic Approach ◽  
Symptomatic Treatment ◽  
Therapeutic Interventions ◽  
Dopaminergic Therapy ◽  
Comprehensive Management ◽  
The Individual

Parkinson's disease is a progressive neurodegenerative disorder that demands a holistic approach to treatment. Both pharmacologic and nonpharmacologic interventions play an important role in the comprehensive management of this disorder. While levodopa remains the single most effective medication for symptomatic treatment, dopamine agonists are playing an increasingly important role. Motor complications of dopaminergic therapy are a significant issue, particularly in patients with more advanced disease who have been on levodopa for several years. All therapeutic interventions must be tailored to the individual and modified as the disease progresses, with the goal of minimizing significant functional disability as much as possible.

scholarly journals Nicotinamide mononucleotide treatment increases NAD+ levels in an iPSC Model of Parkinson’s Disease

2020 ◽  
Author(s):  
Brett K. Fulleylove-Krause ◽  
Samantha L. Sison ◽  
Allison D. Ebert
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Stem Cell ◽  
Mitochondrial Function ◽  
Dopaminergic Neurons ◽  
Neurodegenerative Disorder ◽  
Motor Deficits ◽  
Severe Motor ◽  
Underlying Mechanisms ◽  
Reduced Nicotinamide Adenine Dinucleotide

AbstractParkinson’s disease (PD) is a common neurodegenerative disorder caused by the loss of dopaminergic neurons in the substantia nigra that leads to severe motor and non-motor deficits. Although the underlying mechanisms of dopaminergic neuron loss is not entirely clear, increasing evidence suggests mitochondrial malfunction as a key contributor to disease pathogenesis. Recently, we found that human PD patient stem cell-derived dopaminergic neurons exhibit reduced nicotinamide adenine dinucleotide (NAD+) levels, an essential cofactor in mitochondrial function and cellular metabolism. In addition, we found that sirtuins, a group of NAD+-dependent deacetylase enzymes that participate in the regulation of mitochondrial function, energy production, and cell survival, displayed decreased activity in PD dopaminergic neurons, thereby suggesting a potential mechanism for dopaminergic loss in PD. Thus, here we tested whether treatment of PD stem cell-derived dopaminergic neurons with an NAD+ precursor could increase NAD+ levels and improve sirtuin activity.

scholarly journals Autonomic Function in Patients With Parkinson’s Disease: From Rest to Exercise

2021 ◽  
Vol 12 ◽  
Author(s):  
Jeann L. Sabino-Carvalho ◽  
James P. Fisher ◽  
Lauro C. Vianna
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Motor Impairment ◽  
Exercise Intolerance ◽  
Motor Nucleus ◽  
Motor Impairments ◽  
Dorsal Motor Nucleus ◽  
Clinically Significant ◽  
Underlying Mechanisms

Parkinson’s disease (PD) is a common neurodegenerative disorder classically characterized by symptoms of motor impairment (e.g., tremor and rigidity), but also presenting with important non-motor impairments. There is evidence for the reduced activity of both the parasympathetic and sympathetic limbs of the autonomic nervous system at rest in PD. Moreover, inappropriate autonomic adjustments accompany exercise, which can lead to inadequate hemodynamic responses, the failure to match the metabolic demands of working skeletal muscle and exercise intolerance. The underlying mechanisms remain unclear, but relevant alterations in several discrete central regions (e.g., dorsal motor nucleus of the vagus nerve, intermediolateral cell column) have been identified. Herein, we critically evaluate the clinically significant and complex associations between the autonomic dysfunction, fatigue and exercise capacity in PD.

scholarly journals Biology of Parkinson's disease: pathogenesis and pathophysiology of a multisystem neurodegenerative disorder

2004 ◽  
Vol 6 (3) ◽  
pp. 259-280 ◽  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Experimental Studies ◽  
Symptomatic Treatment ◽  
Motor Dysfunction ◽  
Motor Impairments ◽  
Neurodegenerative Process ◽  
Midbrain Dopamine ◽  
Proteolytic Stress

Parkinson's disease (PD) is the second most common movement disorder. The characteristic motor impairments - bradykinesia, rigidity, and resting tremor - result from degenerative loss of midbrain dopamine (DA) neurons in the substantia nigra, and are responsive to symptomatic treatment with dopaminergic medications and functional neurosurgery. PD is also the second most common neurodegenerative disorder. Viewed from this perspective, PD is a disorder of multiple functional systems, not simply the motor system, and of multiple neurotransmitter systems, not merely that of DA. The characteristic pathology - intraneuronal Lewy body inclusions and reduced numbers of surviving neurons - is similar in each of the targeted neuron groups, suggesting a common neurodegenerative process. Pathological and experimental studies indicate that oxidative stress, proteolytic stress, and inflammation figure prominently in the pathogenesis of PD. Yet, whether any of these mechanisms plays a causal role in human PD is unknown, because to date we have no proven neuroprotective therapies that slow or reverse disease progression in patients with PD. We are beginning to understand the pathophysiology of motor dysfunction in PD, but its etiopathogenesis as a neurodegenerative disorder remains poorly understood.

scholarly journals GardeninA confers neuroprotection against environmental toxin in a Drosophila model of Parkinson’s disease

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Urmila Maitra ◽  
Thomas Harding ◽  
Qiaoli Liang ◽  
Lukasz Ciesla
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Neurodegenerative Disorder ◽  
Antioxidant Activities ◽  
Disease Model ◽  
Epidemiological Studies ◽  
Disease Etiology ◽  
Environmental Toxin

AbstractParkinson’s disease is an age-associated neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons from the midbrain. Epidemiological studies have implicated exposures to environmental toxins like the herbicide paraquat as major contributors to Parkinson’s disease etiology in both mammalian and invertebrate models. We have employed a paraquat-induced Parkinson’s disease model in Drosophila as an inexpensive in vivo platform to screen therapeutics from natural products. We have identified the polymethoxyflavonoid, GardeninA, with neuroprotective potential against paraquat-induced parkinsonian symptoms involving reduced survival, mobility defects, and loss of dopaminergic neurons. GardeninA-mediated neuroprotection is not solely dependent on its antioxidant activities but also involves modulation of the neuroinflammatory and cellular death responses. Furthermore, we have successfully shown GardeninA bioavailability in the fly heads after oral administration using ultra-performance liquid chromatography and mass spectrometry. Our findings reveal a molecular mechanistic insight into GardeninA-mediated neuroprotection against environmental toxin-induced Parkinson’s disease pathogenesis for novel therapeutic intervention.

scholarly journals Investigation of Autosomal Genetic Sex Differences in Parkinson’s disease

2021 ◽  
Author(s):  
Cornelis Blauwendraat ◽  
Hirotaka Iwaki ◽  
Mary B. Makarious ◽  
Sara Bandres-Ciga ◽  
Hampton Leonard ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Risk ◽  
Neurodegenerative Disorder ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Disease Etiology ◽  
Male And Female ◽  
Y Chromosomes ◽  
Genome Wide

AbstractParkinson’s disease (PD) is a complex neurodegenerative disorder. Males are on average ∼1.5 times more likely to develop PD compared to females. Over the years genome-wide association studies (GWAS) have identified numerous genetic risk factors for PD, however it is unclear whether genetics contribute to disease etiology in a sex-specific manner.In an effort to study sex-specific genetic factors associated with PD, we explored two large genetic datasets from the International Parkinson’s Disease Genomics Consortium and the UK Biobank consisting of 13,020 male PD cases, 7,936 paternal proxy cases, 89,660 male controls, 7,947 female PD cases, 5,473 maternal proxy cases and 90,662 female controls. We performed GWAS meta-analyses to identify distinct patterns of genetic risk contributing to disease in male versus female PD cases.In total 19 genome-wide significant regions were identified, and no sex-specific effects were observed. A high genetic correlation between the male and female PD GWASes was identified (rg=0.877) and heritability estimates were identical between male and female PD cases (∼20%).We did not detect any significant genetic differences between male or female PD cases. Our study does not support the notion that common genetic variation on the autosomes could explain the difference in prevalence of PD between males and females at least when considering the current sample size under study. Further studies are warranted to investigate the genetic architecture of PD explained by X and Y chromosomes and further evaluate environmental effects that could potentially contribute to PD etiology in male versus females.

The Therapeutic Potential of Quercetin in Parkinson’s Disease: Insights into its Molecular and Cellular Regulation

2020 ◽  
Vol 21 (5) ◽  
pp. 509-518 ◽  
Author(s):  
Omid Reza Tamtaji ◽  
Tooba Hadinezhad ◽  
Maryam Fallah ◽  
Arash Rezaei Shahmirzadi ◽  
Mohsen Taghizadeh ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Therapeutic Potential ◽  
Substantia Nigra Pars Compacta ◽  
Cellular Regulation ◽  
Pathophysiological Role ◽  
Underlying Mechanisms ◽  
Treatment Procedures

Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disorder characterized by the progressive death of dopaminergic neurons in the substantia nigra pars compacta (SNc). PD is a multifactorial disorder, with several different factors being suggested to play a synergistic pathophysiological role, including oxidative stress, autophagy, underlying pro-inflammatory events and neurotransmitters abnormalities. Overall, PD can be viewed as the product of a complex interaction of environmental factors acting on a given genetic background. The importance of this subject has gained more attention to discover novel therapies to prevent as well as treat PD. According to previous research, drugs used to treat PD have indicated significant limitations. Therefore, the role of flavonoids has been extensively studied in PD treatment. Quercetin, a plant flavonol from the flavonoid group, has been considered as a supplemental therapy for PD. Quercetin has pharmacological functions in PD by controlling different molecular pathways. Although few studies intended to evaluate the basis for the use of quercetin in the context of PD have been conducted so far, at present, there is very little evidence available addressing the underlying mechanisms of action. Various principal aspects of these treatment procedures remain unknown. Here, currently existing knowledge supporting the use of quercetin for the clinical management of PD has been reviewed.

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