scholarly journals Invertebrate Models Untangle the Mechanism of Neurodegeneration in Parkinson’s Disease

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 407
Author(s):  
Andrei Surguchov
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Drug Targets ◽  
Brain Dysfunction ◽  
Model Organisms ◽  
Cellular Processes ◽  
Neuronal Protein ◽  
Major Player ◽  
New Biomarkers ◽  
Eukaryotic Organisms

Parkinson’s disease (PD) is the second most common neurodegenerative disease, afflicting ~10 million people worldwide. Although several genes linked to PD are currently identified, PD remains primarily an idiopathic disorder. Neuronal protein α-synuclein is a major player in disease progression of both genetic and idiopathic forms of PD. However, it cannot alone explain underlying pathological processes. Recent studies demonstrate that many other risk factors can accelerate or further worsen brain dysfunction in PD patients. Several PD models, including non-mammalian eukaryotic organisms, have been developed to identify and characterize these factors. This review discusses recent findings in three PD model organisms, i.e., yeast, Drosophila, and Caenorhabditis elegans, that opened new mechanisms and identified novel contributors to this disorder. These non-mammalian models share many conserved molecular pathways and cellular processes with humans. New players affecting PD pathogenesis include previously unknown genes/proteins, novel signaling pathways, and low molecular weight substances. These findings might respond to the urgent need to discover novel drug targets for PD treatment and new biomarkers for early diagnostics of this disease. Since the study of neurodegeneration using simple eukaryotic organisms brought a huge amount of information, we include only the most recent or the most important relevant data.

scholarly journals Protective effect of curcumin in transgenic Drosophila melanogaster model of Parkinson’s disease

2012 ◽  
Vol 2 (1) ◽  
pp. 3 ◽  
Author(s):  
Yasir Hasan Siddique ◽  
Gulshan Ara ◽  
Smita Jyoti ◽  
Mohammad Afzal
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Drosophila Melanogaster ◽  
Disease Model ◽  
Model Organisms ◽  
Cellular Processes ◽  
Normal Human ◽  
Climbing Ability ◽  
Dose Dependent

Studies on model organisms have been found to be invaluable in clarifying the cellular and molecular basis of normal cellular processes and disease pathogenesis. Drosophila mutants and transgenes have provided a platform to understand the mechanisms associated with degenerative disease. Studies on the role of polyphenols in protecting against neurodegenerative diseases are limited. In the present study, the effect of curcumin at various doses was studied on the climbing ability of the transgenic <em>Drosophila melanogaster </em>that expresses normal human α-synuclein in the neurons. A significant dose-dependent protection against loss of climbing ability was observed. The results suggest that curcumin can strongly improve the climbing ability of Parkinson’s disease model flies and also supports the utility of this model in studying the symptoms of Parkinson’s disease.

scholarly journals Endoplasmic Reticulum Stress Regulators: New Drug Targets for Parkinson’s Disease

2021 ◽  
pp. 1-10
Author(s):  
Vera Kovaleva ◽  
Mart Saarma
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Er Stress ◽  
Protein Misfolding ◽  
Drug Targets ◽  
Dopamine Neurons ◽  
Drug Candidates ◽  
The Unfolded Protein Response

Parkinson’s disease (PD) pathology involves progressive degeneration and death of vulnerable dopamine neurons in the substantia nigra. Extensive axonal arborisation and distinct functions make this type of neurons particularly sensitive to homeostatic perturbations, such as protein misfolding and Ca2 + dysregulation. Endoplasmic reticulum (ER) is a cell compartment orchestrating protein synthesis and folding, as well as synthesis of lipids and maintenance of Ca2 +-homeostasis in eukaryotic cells. When misfolded proteins start to accumulate in ER lumen the unfolded protein response (UPR) is activated. UPR is an adaptive signalling machinery aimed at relieving of protein folding load in the ER. When UPR is chronic, it can either boost neurodegeneration and apoptosis or cause neuronal dysfunctions. We have recently discovered that mesencephalic astrocyte-derived neurotrophic factor (MANF) exerts its prosurvival action in dopamine neurons and in animal model of PD through the direct binding to UPR sensor inositol-requiring protein 1 alpha (IRE1α) and attenuation of UPR. In line with this, UPR targeting resulted in neuroprotection and neurorestoration in various preclinical PD animal models. Therefore, growth factors (GFs), possessing both neurorestorative activity and restoration of protein folding capacity are attractive as drug candidates for PD treatment especially their blood-brain barrier penetrating analogs and small molecule mimetics. In this review, we discuss ER stress as a therapeutic target to treat PD; we summarize the existing preclinical data on the regulation of ER stress for PD treatment. In addition, we point out the crucial aspects for successful clinical translation of UPR-regulating GFs and new prospective in GFs-based treatments of PD, focusing on ER stress regulation.

scholarly journals Subsecond dopamine fluctuations in human striatum encode superposed error signals about actual and counterfactual reward

2015 ◽  
Vol 113 (1) ◽  
pp. 200-205 ◽  
Author(s):  
Kenneth T. Kishida ◽  
Ignacio Saez ◽  
Terry Lohrenz ◽  
Mark R. Witcher ◽  
Adrian W. Laxton ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Decision Making ◽  
Parkinson's Disease ◽  
Animal Models ◽  
Large Body ◽  
Reward Processing ◽  
Dopamine Neurons ◽  
Model Organisms ◽  
Mammalian Brain ◽  
Prediction Errors

In the mammalian brain, dopamine is a critical neuromodulator whose actions underlie learning, decision-making, and behavioral control. Degeneration of dopamine neurons causes Parkinson’s disease, whereas dysregulation of dopamine signaling is believed to contribute to psychiatric conditions such as schizophrenia, addiction, and depression. Experiments in animal models suggest the hypothesis that dopamine release in human striatum encodes reward prediction errors (RPEs) (the difference between actual and expected outcomes) during ongoing decision-making. Blood oxygen level-dependent (BOLD) imaging experiments in humans support the idea that RPEs are tracked in the striatum; however, BOLD measurements cannot be used to infer the action of any one specific neurotransmitter. We monitored dopamine levels with subsecond temporal resolution in humans (n = 17) with Parkinson’s disease while they executed a sequential decision-making task. Participants placed bets and experienced monetary gains or losses. Dopamine fluctuations in the striatum fail to encode RPEs, as anticipated by a large body of work in model organisms. Instead, subsecond dopamine fluctuations encode an integration of RPEs with counterfactual prediction errors, the latter defined by how much better or worse the experienced outcome could have been. How dopamine fluctuations combine the actual and counterfactual is unknown. One possibility is that this process is the normal behavior of reward processing dopamine neurons, which previously had not been tested by experiments in animal models. Alternatively, this superposition of error terms may result from an additional yet-to-be-identified subclass of dopamine neurons.

The VPS35-D620N mutation is associated with Parkinson's disease and can be a target for gene therapy

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Metabolic Pathways ◽  
Drug Targets ◽  
Neuronal Loss ◽  
Limited Information ◽  
Tau Pathology ◽  
Therapy Goals ◽  
Axonal Degradation

There is evidence that the VPS35 protein impacts degradation of dopaminergic (DA) neuron lifespan and that the D620N mutation is associated with a kind of Parkinson's disease (PD) mimicking idiopathic PD. The incidence of this mutation and the likely pathogenic effects of additional VPS35 variants is unclear. Other unusual VPS35 mutations may put people at risk for Parkinson's disease, but the level of risk has yet to be determined.Due to the functional and genetic links between VPS35 and other PD-associated genes, rare VPS35 variants may be a key extra component in developing the PD phenotype in people with other mutations with inadequate penetration. Genetic association analysis could remedy this issue in the near future.VPS35-associated PD neuropathology is another significant aspect. Since just one D620N mutant carrier has been studied at autopsy to date, limited information is available about the neuropathological spectrum of PD patients with VPS35 mutations. It is yet unknown if neuronal loss in VPS35-related PD occurs just in SNc or affects other brain areas such as locus coeruleus, cortex, hippocampus and other structures. Neuropathology of VPS35-D620N mice models demonstrated severe tau pathology and axonal degradation, but no evidence of SYN inclusions. It's uncertain if PD individuals with VPS35 mutations have the same features.More study on the role of VPS35 in enhancing DA neuron survival is also needed to better understand the metabolic pathways damaged by VPS35 mutations and identify new therapy goals. The D620N VPS35 KI model, paired with the parkinQ311X mouse model, is one of the first monogenic PD models to recapitulate the fundamental PD feature: DA neuronal breakdown in SNc. These mouse models can be used to identify and assess drug targets. Because the neurodegenerative molecular pathways in many types of Parkinson's disease are so similar, drugs that confer neuroprotection in VPS35 models could be studied in other, more common types of Parkinson's disease.

Emerging targets for the diagnosis of Parkinson’s disease: examination of systemic biomarkers

2021 ◽  
Author(s):  
Lara Cheslow ◽  
Adam E Snook ◽  
Scott A Waldman
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Neuronal Damage ◽  
Unmet Need ◽  
Multiple Organ ◽  
The Body ◽  
Organ Systems ◽  
Diagnostic Approaches ◽  
New Biomarkers

Parkinson’s disease (PD) is a highly prevalent and irreversible neurodegenerative disorder that is typically diagnosed in an advanced stage. Currently, there are no approved biomarkers that reliably identify PD patients before they have undergone extensive neuronal damage, eliminating the opportunity for future disease-modifying therapies to intervene in disease progression. This unmet need for diagnostic and therapeutic biomarkers has fueled PD research for decades, but these efforts have not yet yielded actionable results. Recently, studies exploring mechanisms underlying PD progression have offered insights into multisystemic contributions to pathology, challenging the classic perspective of PD as a disease isolated to the brain. This shift in understanding has opened the door to potential new biomarkers from multiple sites in the body. This review focuses on emerging candidates for PD biomarkers in the context of current diagnostic approaches and multiple organ systems that contribute to disease.

scholarly journals PINK1/Parkin Mediated Mitophagy, Ca2+ Signalling, and ER–Mitochondria Contacts in Parkinson’s Disease

2020 ◽  
Vol 21 (5) ◽  
pp. 1772 ◽  
Author(s):  
Lucia Barazzuol ◽  
Flavia Giamogante ◽  
Marisa Brini ◽  
Tito Calì
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Endoplasmic Reticulum ◽  
Neurodegenerative Diseases ◽  
Current Knowledge ◽  
Phosphatase And Tensin Homolog ◽  
Cellular Processes ◽  
Selective Degradation ◽  
Contact Sites ◽  
Tensin Homolog

Endoplasmic reticulum (ER)–mitochondria contact sites are critical structures for cellular function. They are implicated in a plethora of cellular processes, including Ca2+ signalling and mitophagy, the selective degradation of damaged mitochondria. Phosphatase and tensin homolog (PTEN)-induced kinase (PINK) and Parkin proteins, whose mutations are associated with familial forms of Parkinson’s disease, are two of the best characterized mitophagy players. They accumulate at ER–mitochondria contact sites and modulate organelles crosstalk. Alterations in ER–mitochondria tethering are a common hallmark of many neurodegenerative diseases including Parkinson’s disease. Here, we summarize the current knowledge on the involvement of PINK1 and Parkin at the ER–mitochondria contact sites and their role in the modulation of Ca2+ signalling and mitophagy.

scholarly journals Roco Proteins and the Parkinson’s Disease-Associated LRRK2

2018 ◽  
Vol 19 (12) ◽  
pp. 4074 ◽  
Author(s):  
Jingling Liao ◽  
Quyen Hoang
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
G Proteins ◽  
Conformational Changes ◽  
Effector Proteins ◽  
Cellular Processes ◽  
Current State ◽  
Specific Effector ◽  
Unique Domain ◽  
Small G Proteins

Small G-proteins are structurally-conserved modules that function as molecular on-off switches. They function in many different cellular processes with differential specificity determined by the unique effector-binding surfaces, which undergo conformational changes during the switching action. These switches are typically standalone monomeric modules that form transient heterodimers with specific effector proteins in the ‘on’ state, and cycle to back to the monomeric conformation in the ‘off’ state. A new class of small G-proteins called “Roco” was discovered about a decade ago; this class is distinct from the typical G-proteins in several intriguing ways. Their switch module resides within a polypeptide chain of a large multi-domain protein, always adjacent to a unique domain called COR, and its effector kinase often resides within the same polypeptide. As such, the mechanisms of action of the Roco G-proteins are likely to differ from those of the typical G-proteins. Understanding these mechanisms is important because aberrant activity in the human Roco protein LRRK2 is associated with the pathogenesis of Parkinson’s disease. This review provides an update on the current state of our understanding of the Roco G-proteins and the prospects of targeting them for therapeutic purposes.

scholarly journals Evaluating Lipid‐Lowering Drug Targets for Parkinson's Disease Prevention with Mendelian Randomization

2020 ◽  
Vol 88 (5) ◽  
pp. 1043-1047
Author(s):  
Dylan M. Williams ◽  
Sara Bandres‐Ciga ◽  
Karl Heilbron ◽  
David Hinds ◽  
Alastair J. Noyce ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Prevention ◽  
Drug Targets ◽  
Mendelian Randomization ◽  
Lipid Lowering ◽  
Lipid Lowering Drug ◽  
Lowering Drug

scholarly journals The Promise and Challenges of Developing miRNA-Based Therapeutics for Parkinson’s Disease

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 841 ◽  
Author(s):  
Simoneide S. Titze-de-Almeida ◽  
Cristina Soto-Sánchez ◽  
Eduardo Fernandez ◽  
James B. Koprich ◽  
Jonathan M. Brotchie ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Drug Targets ◽  
Fine Tuning ◽  
Dopaminergic Transmission ◽  
Complementary Sequences ◽  
Autonomic Dysfunctions ◽  
Specific Regulation ◽  
Underlying Mechanisms ◽  
Cell Transcriptome

MicroRNAs (miRNAs) are small double-stranded RNAs that exert a fine-tuning sequence-specific regulation of cell transcriptome. While one unique miRNA regulates hundreds of mRNAs, each mRNA molecule is commonly regulated by various miRNAs that bind to complementary sequences at 3’-untranslated regions for triggering the mechanism of RNA interference. Unfortunately, dysregulated miRNAs play critical roles in many disorders, including Parkinson’s disease (PD), the second most prevalent neurodegenerative disease in the world. Treatment of this slowly, progressive, and yet incurable pathology challenges neurologists. In addition to L-DOPA that restores dopaminergic transmission and ameliorate motor signs (i.e., bradykinesia, rigidity, tremors), patients commonly receive medication for mood disorders and autonomic dysfunctions. However, the effectiveness of L-DOPA declines over time, and the L-DOPA-induced dyskinesias commonly appear and become highly disabling. The discovery of more effective therapies capable of slowing disease progression –a neuroprotective agent–remains a critical need in PD. The present review focus on miRNAs as promising drug targets for PD, examining their role in underlying mechanisms of the disease, the strategies for controlling aberrant expressions, and, finally, the current technologies for translating these small molecules from bench to clinics.

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