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.

scholarly journals Impaired D2 receptor-dependent dopaminergic transmission in prefrontal cortex of awake mouse model of Parkinson’s disease

Brain ◽  
2019 ◽  
Vol 142 (10) ◽  
pp. 3099-3115 ◽  
Author(s):  
Mingli Li ◽  
Huadong Xu ◽  
Guoqing Chen ◽  
Suhua Sun ◽  
Qinglong Wang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Prefrontal Cortex ◽  
Mouse Model ◽  
Early Onset ◽  
D2 Receptor ◽  
Motor Symptom ◽  
Dopaminergic Transmission ◽  
Brain Circuits ◽  
Underlying Mechanisms

Anxiety is a major early-onset non-motor symptom in Parkinson’s disease, but the underlying mechanisms remain largely unknown. By imaging brain circuits in an awake parkinsonian mouse model, Li, Xu et al. provide evidence that Parkinson’s disease-associated anxiety is caused by impaired postsynaptic D2 receptor-dependent dopaminergic transmission in prefrontal cortex.

scholarly journals Clinical Markers May Identify Patients at Risk for Early Parkinson’s Disease Dementia: A Prospective Study

2021 ◽  
Vol 36 ◽  
pp. 153331752110213
Author(s):  
Anamaria Jurcau ◽  
Vharoon Sharma Nunkoo
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Binary Logistic Regression ◽  
Binary Logistic Regression Analysis ◽  
Clinical Markers ◽  
Pearson Coefficient ◽  
Autonomic Dysfunctions ◽  
Patients At Risk ◽  
A Prospective Study ◽  
State Examination

Background: The study aims at identifying features predictive of early onset of dementia in Parkinson’s disease (PD). Methods: 103 non-demented PD patients were evaluated on various scales at baseline and 89 patients at 3-year follow-up. Results: By the end of the study 43.8% of patients developed dementia. The development of dementia was linked to the baseline Mini Mental State Examination score (Pearson coefficient r = .404, p = 0.013), the presence of autonomic dysfunctions (r = −.621, p < 0.001) and insomnia (r = −.526, p = 0.001). A binary logistic regression analysis showed that the development of dementia was correlated strongly with the presence of autonomic dysfunctions (95% CI 2.60 to 52.83, p < 0.001), and insomnia (95% CI 0.60 to 0.95, p = 0.017). Conclusion: Patients with signs of autonomic dysfunction and insomnia are at higher risk for developing dementia and deserve closer monitoring of cognitive symptoms.

scholarly journals Electroceutically induced subthalamic high-frequency oscillations and evoked compound activity may explain the mechanism of therapeutic stimulation in Parkinson’s disease

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Musa Ozturk ◽  
Ashwin Viswanathan ◽  
Sameer A. Sheth ◽  
Nuri F. Ince
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Pharmacological Treatment ◽  
High Frequency ◽  
High Frequency Stimulation ◽  
High Frequency Oscillations ◽  
Stimulation Pulse ◽  
Main Challenge ◽  
Frequency Stimulation ◽  
Underlying Mechanisms

AbstractDespite having remarkable utility in treating movement disorders, the lack of understanding of the underlying mechanisms of high-frequency deep brain stimulation (DBS) is a main challenge in choosing personalized stimulation parameters. Here we investigate the modulations in local field potentials induced by electrical stimulation of the subthalamic nucleus (STN) at therapeutic and non-therapeutic frequencies in Parkinson’s disease patients undergoing DBS surgery. We find that therapeutic high-frequency stimulation (130–180 Hz) induces high-frequency oscillations (~300 Hz, HFO) similar to those observed with pharmacological treatment. Along with HFOs, we also observed evoked compound activity (ECA) after each stimulation pulse. While ECA was observed in both therapeutic and non-therapeutic (20 Hz) stimulation, the HFOs were induced only with therapeutic frequencies, and the associated ECA were significantly more resonant. The relative degree of enhancement in the HFO power was related to the interaction of stimulation pulse with the phase of ECA. We propose that high-frequency STN-DBS tunes the neural oscillations to their healthy/treated state, similar to pharmacological treatment, and the stimulation frequency to maximize these oscillations can be inferred from the phase of ECA waveforms of individual subjects. The induced HFOs can, therefore, be utilized as a marker of successful re-calibration of the dysfunctional circuit generating PD symptoms.

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 Restless legs syndrome in Parkinson's disease and increased cardiovascular risk

2018 ◽  
Vol 76 (11) ◽  
pp. 731-735 ◽  
Author(s):  
Maren de Moraes e Silva ◽  
Cezar Henrique Lorenzi ◽  
Blenda Barreto Schneider ◽  
Catherine Enk Fischer Seidel ◽  
Isabela Salomé ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cardiovascular Risk ◽  
Restless Legs Syndrome ◽  
Protective Factor ◽  
Risk Scores ◽  
Dopaminergic Transmission ◽  
Restless Legs ◽  
Cardiovascular Comorbidities ◽  
Framingham Risk

ABSTRACT Restless legs syndrome (RLS) is a disorder commonly found in patients with Parkinson's disease, with descriptions for both conditions impairing dopaminergic transmission in central nervous system. Previous studies in varied populations indicate an association between the presence of RLS and increased cardiovascular risk and, so far, there are no consistent studies of this association in Parkinson's disease. Objective: To analyze the influence of RLS on cardiovascular risk in patients with Parkinson's disease. Methods: We reviewed the medical records of 202 patients diagnosed with Parkinson's disease and verified the presence of RLS, cardiovascular comorbidities, blood pressure measurements, lipid profiles and Framingham Risk Scores. Results: Statistically significant higher values of total cholesterol were found for the RLS group (mean 216.6 mg/dL), as well as for LDL cholesterol (mean 145 mg/dL). No statistical difference was found among the other factors. Conclusion: Patients with Parkinson's disease and RLS have a higher prevalence of dyslipidemia than patients without RLS, suggesting a correlation between restless legs and hyperlipidemia. It is questioned whether the dopaminergic substrate is the main factor in the genesis of the syndrome, as even with the use of dopaminergic agonists by both groups, it was possible to observe differences between groups. The hypothesis of the real interference of the syndrome treatment as a protective factor for cardiovascular risk was generated.

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.

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.

Electroceutically induced subthalamic high frequency oscillations and evoked compound activity may explain the mechanism of therapeutic stimulation in Parkinson's Disease

2020 ◽  
Author(s):  
Musa Ozturk ◽  
Ashwin Viswanathan ◽  
Sameer Sheth ◽  
Nuri Ince
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Pharmacological Treatment ◽  
High Frequency ◽  
High Frequency Stimulation ◽  
High Frequency Oscillations ◽  
Stimulation Pulse ◽  
Main Challenge ◽  
Frequency Stimulation ◽  
Underlying Mechanisms

Abstract Despite having remarkable utility in treating movement disorders, the lack of understanding of the underlying mechanisms of high-frequency deep brain stimulation (DBS) is a main challenge in choosing personalized stimulation parameters. Here we investigate the modulations in local field potentials induced by therapeutic and non-therapeutic electrical stimulation of the subthalamic nucleus (STN) in Parkinson’s disease patients undergoing DBS surgery. We find that therapeutic high-frequency stimulation (130-180 Hz) induces high-frequency oscillations (~300 Hz, HFO) similar to those observed with pharmacological treatment. Along with HFOs, we also observed evoked compound activity (ECA) after each stimulation pulse. While ECA was observed in both therapeutic and non-therapeutic (20Hz) stimulation, the HFOs were induced only with therapeutic frequencies and the associated ECA were significantly more resonant. The relative degree of enhancement in the HFO power was related to the interaction of stimulation pulse with the phase of ECA.We propose that high-frequency STN-DBS tunes the neural oscillations to their healthy/treated state, similar to pharmacological treatment, and the stimulation frequency to maximize these oscillations can be inferred from the phase of ECA waveforms of individual subjects. The induced HFOs can, therefore, be utilized as a marker of successful re-calibration of the dysfunctional circuit generating PD symptoms.

scholarly journals Investigating the convergent mechanisms between Major Depressive Disorder and Parkinson’s disease

2020 ◽  
Author(s):  
Angela A Tran ◽  
Myra De Smet ◽  
Gary D. Grant ◽  
Tien K. Khoo ◽  
Dean L Pountney
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Cell Activation ◽  
Glutamate Excitotoxicity ◽  
Major Depressive ◽  
Glial Cell Activation ◽  
Underlying Mechanisms ◽  
The Brain

Major depressive disorder (MDD) affects more than cognition, having a temporal relationship with neuroinflammatory pathways of Parkinson’s disease (PD). Although this association is supported by epidemiological and clinical studies, the underlying mechanisms are unclear. Microglia and astrocytes play crucial roles in the pathophysiology of both MDD and PD. In PD, these cells can be activated by misfolded forms of the protein α-synuclein to release cytokines that can interact with multiple different physiological processes to produce depressive symptoms, including monoamine transport and availability, the hypothalamus-pituitary axis, and neurogenesis. In MDD, glial cell activation can be induced by peripheral inflammatory agents that cross the blood brain barrier and/or c-Fos signaling from neurons. The resulting neuroinflammation can cause neurodegeneration due to oxidative stress and glutamate excitotoxicity, contributing to PD pathology. Astrocytes are another major link due to their recognised role in the glymphatic clearance mechanism. Research suggesting that MDD causes astrocytic destruction or structural atrophy highlight the possibility that accumulation of α-synuclein in the brain is facilitated as the brain cannot adequately clear the protein aggregates. This review examines research into the overlapping pathophysiology of MDD and PD with particular focus on the roles of glial cells and neuroinflammation.

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