scholarly journals Drosophila Models of Parkinson's Disease: Discovering Relevant Pathways and Novel Therapeutic Strategies

2011 ◽  
Vol 2011 ◽  
pp. 1-14 ◽  
Author(s):  
Verónica Muñoz-Soriano ◽  
Nuria Paricio
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Neurodegenerative Disorder ◽  
Model Organism ◽  
Disease Process ◽  
Therapeutic Strategies ◽  
Progressive Loss ◽  
Novel Therapeutic Strategies ◽  
Drosophila Models

Parkinson's disease (PD) is the second most common neurodegenerative disorder and is mainly characterized by the selective and progressive loss of dopaminergic neurons, accompanied by locomotor defects. Although most PD cases are sporadic, several genes are associated with rare familial forms of the disease. Analyses of their function have provided important insights into the disease process, demonstrating that three types of cellular defects are mainly involved in the formation and/or progression of PD: abnormal protein aggregation, oxidative damage, and mitochondrial dysfunction. These studies have been mainly performed in PD models created in mice, fruit flies, and worms. Among them, Drosophila has emerged as a very valuable model organism in the study of either toxin-induced or genetically linked PD. Indeed, many of the existing fly PD models exhibit key features of the disease and have been instrumental to discover pathways relevant for PD pathogenesis, which could facilitate the development of therapeutic strategies.

Parkinson's Disease

2019 ◽  
pp. 252-273 ◽  
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.

scholarly journals Drosophila Models of Sporadic Parkinson’s Disease

2018 ◽  
Vol 19 (11) ◽  
pp. 3343 ◽  
Author(s):  
Emi Nagoshi
Keyword(s):  
Risk Factors ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Future Perspectives ◽  
Progressive Loss ◽  
New Findings ◽  
Sporadic Parkinson’S Disease ◽  
Preclinical Animal Models ◽  
Drosophila Models

Parkinson’s disease (PD) is the most common cause of movement disorders and is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. It is increasingly recognized as a complex group of disorders presenting widely heterogeneous symptoms and pathology. With the exception of the rare monogenic forms, the majority of PD cases result from an interaction between multiple genetic and environmental risk factors. The search for these risk factors and the development of preclinical animal models are in progress, aiming to provide mechanistic insights into the pathogenesis of PD. This review summarizes the studies that capitalize on modeling sporadic (i.e., nonfamilial) PD using Drosophila melanogaster and discusses their methodologies, new findings, and future perspectives.

scholarly journals The Promise of the Zebrafish Model for Parkinson’s Disease: Today’s Science and Tomorrow’s Treatment

2021 ◽  
Vol 12 ◽  
Author(s):  
Khairiah Razali ◽  
Noratikah Othman ◽  
Mohd Hamzah Mohd Nasir ◽  
Abd Almonem Doolaanea ◽  
Jaya Kumar ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Large Scale ◽  
Neurodegenerative Disorder ◽  
Model Organism ◽  
The Elderly ◽  
Zebrafish Model ◽  
Mao B ◽  
Viable Model

The second most prevalent neurodegenerative disorder in the elderly is Parkinson’s disease (PD). Its etiology is unclear and there are no available disease-modifying medicines. Therefore, more evidence is required concerning its pathogenesis. The use of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is the basis of most animal models of PD. MPTP is metabolized by monoamine oxidase B (MAO B) to MPP + and induces the loss of dopaminergic neurons in the substantia nigra in mammals. Zebrafish have been commonly used in developmental biology as a model organism, but owing to its perfect mix of properties, it is now emerging as a model for human diseases. Zebrafish (Danio rerio) are cheap and easy to sustain, evolve rapidly, breed transparent embryos in large amounts, and are readily manipulated by different methods, particularly genetic ones. Furthermore, zebrafish are vertebrate species and mammalian findings obtained from zebrafish may be more applicable than those derived from genetic models of invertebrates such as Drosophila melanogaster and Caenorhabditis elegans. The resemblance cannot be taken for granted, however. The goal of the present review article is to highlight the promise of zebrafish as a PD animal model. As its aminergic structures, MPTP mode of action, and PINK1 roles mimic those of mammalians, zebrafish seems to be a viable model for studying PD. The roles of zebrafish MAO, however, vary from those of the two types of MAO present in mammals. The benefits unique to zebrafish, such as the ability to perform large-scale genetic or drug screens, should be exploited in future experiments utilizing zebrafish PD models.

scholarly journals Deconstructing the molecular genetics behind the PINK1/Parkin axis in Parkinson’s disease using Drosophila melanogaster as a model organism

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Suchita Ganesan ◽  
Venkatachalam Deepa Parvathi
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Neurodegenerative Disorder ◽  
Ectopic Expression ◽  
Model Organism ◽  
E3 Ligase ◽  
Mitochondrial Morphology ◽  
Main Body

Abstract Background Parkinson’s disease (PD) is a multifactorial neurodegenerative disorder marked by the death of nigrostriatal dopaminergic neurons in response to the compounding effects of oxidative stress, mitochondrial dysfunction and protein aggregation. Transgenic Drosophila models have been used extensively to decipher the underlying genetic interactions that exacerbate neural health in PD. Autosomal recessive forms of the disease have been linked to mutations in the serine/threonine kinase PINK1(PTEN-Induced Putative Kinase 1) and E3 ligase Parkin, which function in an axis that is conserved in flies. This review aims to probe the current understanding of PD pathogenesis via the PINK1/Parkin axis while underscoring the importance of several molecular and pharmacologic rescues brought to light through studies in Drosophila. Main body Mutations in PINK1 and Parkin have been shown to affect the axonal transport of mitochondria within dopaminergic neurons and perturb the balance between mitochondrial fusion/fission resulting in abnormal mitochondrial morphology. As per studies in flies, ectopic expression of Fwd kinase and Atg-1 to promote fission and mitophagy while suppressing fusion via MUL1 E3 ligase may aid to halt mitochondrial aggregation and prolong the survival of dopaminergic neurons. Furthermore, upregulation of Hsp70/Hsp90 chaperone systems (Trap1, CHIP) to target misfolded mitochondrial respiratory complexes may help to preserve their bioenergetic capacity. Accumulation of reactive oxygen species as a consequence of respiratory complex dysfunction or antioxidant enzyme deficiency further escalates neural death by inducing apoptosis, lipid peroxidation and DNA damage. Fly studies have reported the induction of canonical Wnt signalling to enhance the activity of transcriptional co-activators (PGC1α, FOXO) which induce the expression of antioxidant enzymes. Enhancing the clearance of free radicals via uncoupling proteins (UCP4) has also been reported to ameliorate oxidative stress-induced cell death in PINK1/Parkin mutants. Conclusion While these novel mechanisms require validation through mammalian studies, they offer several explanations for the factors propagating dopaminergic death as well as promising insights into the therapeutic importance of transgenic fly models in PD.

Current Therapeutic Strategies and Perspectives for Neuroprotection in Parkinson’s Disease

2020 ◽  
Vol 26 (37) ◽  
pp. 4738-4746
Author(s):  
Mohan K. Ghanta ◽  
P. Elango ◽  
Bhaskar L. V. K. S.
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Early Diagnosis ◽  
Neurodegenerative Disorder ◽  
Therapeutic Strategies ◽  
Neuroprotective Agents ◽  
Striatal Neurons ◽  
The Status ◽  
Advanced Stages ◽  
Dopaminergic Pathways

Parkinson’s disease is a progressive neurodegenerative disorder of dopaminergic striatal neurons in basal ganglia. Treatment of Parkinson’s disease (PD) through dopamine replacement strategies may provide improvement in early stages and this treatment response is related to dopaminergic neuronal mass which decreases in advanced stages. This treatment failure was revealed by many studies and levodopa treatment became ineffective or toxic in chronic stages of PD. Early diagnosis and neuroprotective agents may be a suitable approach for the treatment of PD. The essentials required for early diagnosis are biomarkers. Characterising the striatal neurons, understanding the status of dopaminergic pathways in different PD stages may reveal the effects of the drugs used in the treatment. This review updates on characterisation of striatal neurons, electrophysiology of dopaminergic pathways in PD, biomarkers of PD, approaches for success of neuroprotective agents in clinical trials. The literature was collected from the articles in database of PubMed, MedLine and other available literature resources.

scholarly journals Novel Immunotherapeutic Approaches to Target Alpha-Synuclein and Related Neuroinflammation in Parkinson’s Disease

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 105 ◽  
Author(s):  
Maria Zella ◽  
Judith Metzdorf ◽  
Friederike Ostendorf ◽  
Fabian Maass ◽  
Siegfried Muhlack ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Glial Cell ◽  
Dopaminergic Neurons ◽  
Basic Research ◽  
Alpha Synuclein ◽  
Models Of Disease ◽  
Novel Therapeutic Strategies ◽  
Lymphocyte Populations

The etiology of Parkinson’s disease (PD) is significantly influenced by disease-causing changes in the protein alpha-Synuclein (aSyn). It can trigger and promote intracellular stress and thereby impair the function of dopaminergic neurons. However, these damage mechanisms do not only extend to neuronal cells, but also affect most glial cell populations, such as astroglia and microglia, but also T lymphocytes, which can no longer maintain the homeostatic CNS milieu because they produce neuroinflammatory responses to aSyn pathology. Through precise neuropathological examination, molecular characterization of biomaterials, and the use of PET technology, it has been clearly demonstrated that neuroinflammation is involved in human PD. In this review, we provide an in-depth overview of the pathomechanisms that aSyn elicits in models of disease and focus on the affected glial cell and lymphocyte populations and their interaction with pathogenic aSyn species. The interplay between aSyn and glial cells is analyzed both in the basic research setting and in the context of human neuropathology. Ultimately, a strong rationale builds up to therapeutically reduce the burden of pathological aSyn in the CNS. The current antibody-based approaches to lower the amount of aSyn and thereby alleviate neuroinflammatory responses is finally discussed as novel therapeutic strategies for PD.

scholarly journals Stem Cell Therapy: A Promising Treatment of Parkinson’s Diseases

2021 ◽  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Progression ◽  
Dopaminergic Neurons ◽  
Cellular Therapy ◽  
Neurodegenerative Disorder ◽  
Neuronal Degeneration ◽  
Cell Types ◽  
Parkinson’S Diseases ◽  
Multipotent Mesenchymal Stem Cells

The neurodegenerative disorder is a prolonged persistence curse and effect on economic and physical challenges in an aging world. Parkinson has come in the second category of disability disorders and associated with progressive dopaminergic neuronal degeneration with severe motor complications. It is an observation that gradual disease progression causes 70% degeneration of striatal dopaminergic neurons. Globally there are around 7-10 million patients with Parkinson's disease, however, there are huge efforts for therapeutic improvement. According to studies, no single molecular pathway was pointed out as a single etiology to control disease progression due to a lack of targeted therapeutic strategies. Previously implemented symptomatic treatments include L-dopa (L-3,4-dihydroxyphenylalanine), deep brain stimulation, and the surgical insertion of a medical device. This leads to dyskinesia, dystonia and a higher risk of major surgical complications respectively. However, not all the above-mentioned therapies cannot regenerate the dopaminergic neurons in Parkinson’s disease patients. Recent advances in the field of cellular therapy have shown promising outcomes by differentiation of multipotent mesenchymal stem cells into dopaminergic neurons under the influence of a regenerative substance. In this review, we have discussed the differentiation of dopaminergic neurons by using different cell types that can be used as a cellular therapeutic approach for Parkinson’s disease. The information was collected through a comprehensive search using the keywords, “Parkinson Disease, Dopamine, Brain derived neurotrophic factor and neuron from reliable search engines, PubMed, Google Scholar and Medline reviews from the year 2010 to 2020.

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 TFE3-Mediated Autophagy is Involved in Dopaminergic Neurodegeneration in Parkinson’s Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
Xin He ◽  
Yue Xie ◽  
Qiongping Zheng ◽  
Zeyu Zhang ◽  
Shanshan Ma ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Transcription Factor ◽  
Dopaminergic Neurons ◽  
Essential Role ◽  
Dopaminergic Neurodegeneration ◽  
Promising Strategy ◽  
Progressive Loss ◽  
Mptp Model

Impairment of autophagy has been strongly implicated in the progressive loss of nigral dopaminergic neurons in Parkinson’s disease (PD). Transcription factor E3 (TFE3), an MiTF/TFE family transcription factor, has been identified as a master regulator of the genes that are associated with lysosomal biogenesis and autophagy. However, whether TFE3 is involved in parkinsonian neurodegeneration remains to be determined. In this study, we found decreased TFE3 expression in the nuclei of the dopaminergic neurons of postmortem human PD brains. Next, we demonstrated that TFE3 knockdown led to autophagy dysfunction and neurodegeneration of dopaminergic neurons in mice, implying that reduction of nuclear TFE3 may contribute to autophagy dysfunction-mediated cell death in PD. Further, we showed that enhancement of autophagy by TFE3 overexpression dramatically reversed autophagy downregulation and dopaminergic neurons loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. Taken together, these findings demonstrate that TFE3 plays an essential role in maintaining autophagy and the survival of dopaminergic neurons, suggesting TFE3 activation may serve as a promising strategy for PD therapy.

scholarly journals Detection of Parkinson’s Disease from 3T T1 Weighted MRI Scans Using 3D Convolutional Neural Network

Diagnostics ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 402
Author(s):  
Sabyasachi Chakraborty ◽  
Satyabrata Aich ◽  
Hee-Cheol Kim
Keyword(s):  
Neural Network ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Convolutional Neural Network ◽  
Dopaminergic Neurons ◽  
Aging Population ◽  
Substantia Nigra Pars Compacta ◽  
Progressive Loss ◽  
Mri Scans ◽  
Magnetic Resonance Imaging Mri

Parkinson’s Disease is a neurodegenerative disease that affects the aging population and is caused by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). With the onset of the disease, the patients suffer from mobility disorders such as tremors, bradykinesia, impairment of posture and balance, etc., and it progressively worsens in the due course of time. Additionally, as there is an exponential growth of the aging population in the world the number of people suffering from Parkinson’s Disease is increasing and it levies a huge economic burden on governments. However, until now no therapeutic method has been discovered for completely eradicating the disease from a person’s body after it’s onset. Therefore, the early detection of Parkinson’s Disease is of paramount importance to tackle the progressive loss of dopaminergic neurons in patients to serve them with a better life. In this study, 3T T1-weighted MRI scans were acquired from the Parkinson’s Progression Markers Initiative (PPMI) database of 406 subjects from baseline visit, where 203 were healthy and 203 were suffering from Parkinson’s Disease. Following data pre-processing, a 3D convolutional neural network (CNN) architecture was developed for learning the intricate patterns in the Magnetic Resonance Imaging (MRI) scans for the detection of Parkinson’s Disease. In the end, it was observed that the developed 3D CNN model performed superiorly by completely aligning with the hypothesis of the study and plotted an overall accuracy of 95.29%, average recall of 0.943, average precision of 0.927, average specificity of 0.9430, f1-score of 0.936, and Receiver Operating Characteristic—Area Under Curve (ROC-AUC) score of 0.98 for both the classes respectively.

Sign in / Sign up

Export Citation Format

Share Document