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 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 Peripheral Delivery of Neural Precursor Cells Ameliorates Parkinson’s Disease-Associated Pathology

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1359 ◽  
Author(s):  
Edwards III ◽  
Gamez ◽  
Armijo ◽  
Kramm ◽  
Morales ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Stem Cell ◽  
Motor Function ◽  
Dopaminergic Neurons ◽  
Neurodegenerative Disorder ◽  
Clinical Signs ◽  
Alpha Synuclein ◽  
Neuroinflammatory Response ◽  
Impaired Motor Function

: Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by loss of motor control due to a wide loss of dopaminergic neurons along the nigro-striatal pathway. Some of the mechanisms that contribute to this cell death are inflammation, oxidative stress, and misfolded alpha-synuclein-induced toxicity. Current treatments are effective at managing the early motor symptoms of the disease, but they become ineffective over time and lead to adverse effects. Previous research using intracerebral stem cell therapy for treatment of PD has provided promising results; however, this method is very invasive and is often associated with unacceptable side effects. In this study, we used an MPTP-injected mouse model of PD and intravenously administered neural precursors (NPs) obtained from mouse embryonic and mesenchymal stem cells. Clinical signs and neuropathology were assessed. Female mice treated with NPs had improved motor function and reduction in the neuroinflammatory response. In terms of safety, there were no tumorigenic formations or any detectable adverse effect after treatment. Our results suggest that peripheral administration of stem cell-derived NPs may be a promising and safe therapy for the recovery of impaired motor function and amelioration of brain pathology in PD.

scholarly journals Single cell transcriptomics of human PINK1 iPSC differentiation dynamics reveal a core network of Parkinson’s disease

2020 ◽  
Author(s):  
Gabriela Novak ◽  
Dimitrios Kyriakis ◽  
Kamil Grzyb ◽  
Michela Bernini ◽  
Steven Finkbeiner ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Single Cell ◽  
Dopaminergic Neurons ◽  
Neurodegenerative Disorder ◽  
Mitochondrial Protein ◽  
Core Network ◽  
Protein Coding ◽  
New Interpretation ◽  
Underlying Mechanisms

Abstract Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder, characterized by the loss of dopaminergic neurons (mDA) in the midbrain. The heterogenous pathology and complex underlying mechanisms are only partly understood and there is no treatment able to reverse PD progression. Here, we targeted the disease mechanisms by focusing on the ILE368ASN mutation within the PINK1 (PARK6) gene and systematically characterized midbrain dopaminergic neurons obtained from human induced pluripotent stem cells (iPSCs). Single-cell RNA sequencing (RNAseq) and pairwise analysis of gene expression identified genes consistently differentially expressed during the mDA neuron differentiation process. Subsequent network analysis revealed that these genes form a core network, which interacts with all known 19 protein-coding Parkinson’s disease-associated genes and includes ubiquitination, mitochondrial, protein processing, RNA metabolism, and secretory pathways as important subnetworks. Our findings indicate a unified network underlying PD pathology and offers new interpretation of the phenotypic heterogeneity of 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.

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 Cav2.3 channels contribute to dopaminergic neuron loss in a model of Parkinson’s disease

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Julia Benkert ◽  
Simon Hess ◽  
Shoumik Roy ◽  
Dayne Beccano-Kelly ◽  
Nicole Wiederspohn ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Neuronal Viability ◽  
Age Dependent ◽  
Human Ipsc ◽  
Reduced Activity ◽  
Dopaminergic Neuron Loss ◽  
Full Protection

Abstract Degeneration of dopaminergic neurons in the substantia nigra causes the motor symptoms of Parkinson’s disease. The mechanisms underlying this age-dependent and region-selective neurodegeneration remain unclear. Here we identify Cav2.3 channels as regulators of nigral neuronal viability. Cav2.3 transcripts were more abundant than other voltage-gated Ca2+ channels in mouse nigral neurons and upregulated during aging. Plasmalemmal Cav2.3 protein was higher than in dopaminergic neurons of the ventral tegmental area, which do not degenerate in Parkinson’s disease. Cav2.3 knockout reduced activity-associated nigral somatic Ca2+ signals and Ca2+-dependent after-hyperpolarizations, and afforded full protection from degeneration in vivo in a neurotoxin Parkinson’s mouse model. Cav2.3 deficiency upregulated transcripts for NCS-1, a Ca2+-binding protein implicated in neuroprotection. Conversely, NCS-1 knockout exacerbated nigral neurodegeneration and downregulated Cav2.3. Moreover, NCS-1 levels were reduced in a human iPSC-model of familial Parkinson’s. Thus, Cav2.3 and NCS-1 may constitute potential therapeutic targets for combatting Ca2+-dependent neurodegeneration in Parkinson’s disease.

scholarly journals Editorial for the Special Issue “Animal Models of Parkinson’s Disease and Related Disorders”

2020 ◽  
Vol 21 (12) ◽  
pp. 4250
Author(s):  
Yuzuru Imai
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Animal Models ◽  
Dopaminergic Neurons ◽  
Neurodegenerative Disorder ◽  
Motor Dysfunction ◽  
Special Issue ◽  
Midbrain Dopaminergic Neurons ◽  
Age Dependent ◽  
Common Neurodegenerative Disorder

Parkinson’s disease (PD) is the second most common neurodegenerative disorder characterized by age-dependent motor dysfunction and degeneration of the midbrain dopaminergic neurons [...]

Ethical Criteria for Human Trials of Stem-Cell-Derived Dopaminergic Neurons in Parkinson's Disease

2015 ◽  
Vol 6 (1) ◽  
pp. 52-60 ◽  
Author(s):  
Samia A. Hurst ◽  
Alex Mauron ◽  
Shahan Momjian ◽  
Pierre R. Burkhard
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Stem Cell ◽  
Dopaminergic Neurons ◽  
Human Trials ◽  
Ethical Criteria

scholarly journals Using Human Pluripotent Stem Cell–Derived Dopaminergic Neurons to Evaluate Candidate Parkinson’s Disease Therapeutic Agents in MPP+ and Rotenone Models

2013 ◽  
Vol 18 (5) ◽  
pp. 522-533 ◽  
Author(s):  
Jun Peng ◽  
Qiuyue Liu ◽  
Mahendra S. Rao ◽  
Xianmin Zeng
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Stem Cell ◽  
Dopaminergic Neurons ◽  
Pluripotent Stem Cell ◽  
Neuroprotective Effect ◽  
Neuronal Cell ◽  
Rapid Screening ◽  
Patient Specific ◽  
Human Pluripotent Stem Cell

To begin to develop a high-throughput assay system to evaluate potential small-molecule therapy for Parkinson’s disease (PD), we have performed a low-throughput assay with a small number of compounds using human pluripotent stem cell–derived dopaminergic neurons. We first evaluated the role of 44 compounds known to work in rodent systems in a 1-methyl-4-phenylpyridinium (MPP+) assay in a 96-well format using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay as a readout for neuroprotection. Glial cell–derived neurotrophic factor was used as a positive control because of its well-documented neuroprotective effect on dopaminergic neurons, and two concentrations of each drug were tested. Of 44 compounds screened, 16 showed a neuroprotective effect at one or both dosages tested. A dose-response curve of a subset of the 16 positives was established in the MPP+ model. In addition, we validated neuroprotective effects of these compounds in a rotenone-induced dopaminergic neuronal cell death, another established model for PD. Our human primary dopaminergic neuron-based assays provide a platform for rapid screening and/or validation of potential neuroprotective agents in PD treatment using patient-specific cells and show the importance of using human cells for such assays.

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.

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