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International Journal of Molecular... Jul 2022Parkinson's disease (PD), the second most common neurodegenerative disorder worldwide, is characterized by dopaminergic neuron degeneration and α-synuclein aggregation... (Review)
Review
Parkinson's disease (PD), the second most common neurodegenerative disorder worldwide, is characterized by dopaminergic neuron degeneration and α-synuclein aggregation in the substantia nigra pars compacta of the midbrain. Emerging evidence has shown that dietary intake affects the microbial composition in the gut, which in turn contributes to, or protects against, the degeneration of dopaminergic neurons in affected regions of the brain. More specifically, the Mediterranean diet and Western diet, composed of varying amounts of proteins, carbohydrates, and fats, exert contrasting effects on PD pathophysiology via alterations in the gut microbiota and dopamine levels. Interestingly, the negative changes in the gut microbiota of patients with PD parallel changes that are seen in individuals that consume a Western diet, and are opposite to those that adhere to a Mediterranean diet. In this review, we first examine the role of prominent food groups on dopamine bioavailability, how they modulate the composition and function of the gut microbiota and the subsequent effects on PD and obesity pathophysiology. We then highlight evidence on how microbiota transplant and weight loss surgery can be used as therapeutic tools to restore dopaminergic deficits through optimizing gut microbial composition. In the process, we revisit dietary metabolites and their role in therapeutic approaches involving dopaminergic pathways. Overall, understanding the role of nutrition on dopamine bioavailability and gut microbiota in dopamine-related pathologies such as PD will help develop more precise therapeutic targets to rescue dopaminergic deficits in neurologic and metabolic disorders.
Topics: Bariatric Surgery; Dopamine; Dopaminergic Neurons; Gastrointestinal Microbiome; Humans; Obesity; Parkinson Disease
PubMed: 35886849
DOI: 10.3390/ijms23147503 -
Molecular Brain Jun 2022Parkinson's disease, the second most common neurodegenerative disorder, is characterized by the loss of nigrostriatal dopamine neurons. FBXO7 (F-box protein only 7)...
Parkinson's disease, the second most common neurodegenerative disorder, is characterized by the loss of nigrostriatal dopamine neurons. FBXO7 (F-box protein only 7) (PARK15) mutations cause early-onset Parkinson's disease. FBXO7 is a subunit of the SCF (SKP1/cullin-1/F-box protein) E3 ubiquitin ligase complex, but its neuronal relevance and function have not been elucidated. To determine its function in neurons, we generated neuronal cell-specific FBXO7 conditional knockout mice (FBXO7: Nestin-Cre) by crossing previously characterized FBXO7 floxed mice (FBXO7) with Nestin-Cre mice (Nestin-Cre). The resultant Fbxo7: Nestin-Cre mice showed juvenile motor dysfunction, including hindlimb defects and decreased numbers of dopaminergic neurons. Fragmented mitochondria were observed in dopaminergic and cortical neurons. Furthermore, p62- and synuclein-positive Lewy body-like aggregates were identified in neurons. Our findings highlight the unexpected role of the homeostatic level of p62, which is regulated by a non-autophagic system that includes the ubiquitin-proteasome system, in controlling intracellular inclusion body formation. These data indicate that the pathologic processes associated with the proteolytic and mitochondrial degradation systems play a crucial role in the pathogenesis of PD.
Topics: Animals; Dopaminergic Neurons; F-Box Proteins; Lewy Bodies; Mice; Mice, Knockout; Mitochondria; Nestin; Parkinson Disease
PubMed: 35701754
DOI: 10.1186/s13041-022-00936-5 -
Nutritional Neuroscience Jun 2020Ginger and its compound, 6-shogaol, have been known for improving gastrointestinal (GI) function and reducing inflammatory responses in GI tract. Recently, the...
Ginger and its compound, 6-shogaol, have been known for improving gastrointestinal (GI) function and reducing inflammatory responses in GI tract. Recently, the treatment of GI dysfunction has been recognized as an important part of the management of neurodegenerative diseases, especially for Parkinson's disease (PD). In this study, we investigated whether ginger and 6-shogaol attenuate disruptions induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on the intestinal barrier and the enteric dopaminergic neurons. C57BL/6J mice received MPTP (30 mg/kg) for 5 days to induce GI alterations. Ginger (30, 100, 300 mg/kg) and 6-shogaol (10 mg/kg) were treated by gavage feeding for 15 days including the period of MPTP injection. Ginger and 6-shogaol protected intestinal tight junction proteins disrupted by MPTP in mouse colon. In addition, ginger and 6-shogaol suppressed the increase of inducible nitric oxide synthase, cyclooxygenase-2, TNF-α and IL-1β activated by macrophage. Moreover, ginger and 6-shogaol suppressed the MPTP-induced enteric dopaminergic neuronal damage via increasing the cell survival signaling pathway. These results indicate that ginger and 6-shogaol restore the disruption of intestinal integrity and enteric dopaminergic neurons in an MPTP-injected mouse PD model by inhibiting the processes of inflammation and apoptosis, suggesting that they may attenuate the GI dysfunction in PD patients.
Topics: Animals; Catechols; Colitis; Dopaminergic Neurons; Zingiber officinale; Intestinal Mucosa; MPTP Poisoning; Male; Mice, Inbred C57BL; Plant Extracts; Protective Agents; Signal Transduction; Tight Junctions
PubMed: 30230979
DOI: 10.1080/1028415X.2018.1520477 -
Neuropeptides Jun 2023Parkinson's disease is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta. The surviving nigral dopaminergic neurons... (Review)
Review
Parkinson's disease is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta. The surviving nigral dopaminergic neurons display altered spontaneous firing activity in Parkinson's disease. The firing rate of nigral dopaminergic neurons decreases long before complete neuronal death and the appearance of parkinsonian symptoms. A mild stimulation could rescue dopaminergic neurons from death and in turn play neuroprotective effects. Several neuropeptides, including cholecystokinin (CCK), ghrelin, neurotensin, orexin, tachykinins and apelin, within the substantia nigra pars compacta play important roles in the modulation of spontaneous firing activity of dopaminergic neurons and therefore involve motor control and motor disorders. Here, we review neuropeptide-induced modulation of the firing properties of nigral dopaminergic neurons. This review may provide a background to guide further investigations into the involvement of neuropeptides in movement control by modulating firing activity of nigral dopaminergic neurons in Parkinson's disease.
Topics: Humans; Dopaminergic Neurons; Parkinson Disease; Neuroprotection; Substantia Nigra; Neuropeptides
PubMed: 37087783
DOI: 10.1016/j.npep.2023.102337 -
International Journal of Molecular... Apr 2018Oxidative stress is increasingly recognized as a central event contributing to the degeneration of dopaminergic neurons in the pathogenesis of Parkinson's disease (PD).... (Review)
Review
Oxidative stress is increasingly recognized as a central event contributing to the degeneration of dopaminergic neurons in the pathogenesis of Parkinson's disease (PD). Although reactive oxygen species (ROS) production is implicated as a causative factor in PD, the cellular and molecular mechanisms linking oxidative stress with dopaminergic neuron death are complex and not well characterized. The primary insults cause the greatest production of ROS, which contributes to oxidative damage by attacking all macromolecules, including lipids, proteins and nucleic acids, leading to defects in their physiological function. Consequently, the defects in these macromolecules result in mitochondrial dysfunction and neuroinflammation, which subsequently enhance the production of ROS and ultimately neuronal damage. The interaction between these various mechanisms forms a positive feedback loop that drives the progressive loss of dopaminergic neurons in PD, and oxidative stress‑mediated neuron damage appears to serve a central role in the neurodegenerative process. Thus, understanding the cellular and molecular mechanisms by which oxidative stress contributes to the loss of dopaminergic neurons may provide a promising therapeutic approach in PD treatment.
Topics: Animals; Cell Death; Dopaminergic Neurons; Humans; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Oxidative Stress; Parkinson Disease; Reactive Oxygen Species
PubMed: 29393357
DOI: 10.3892/ijmm.2018.3406 -
Methods in Molecular Biology (Clifton,... 2022The use of patient-derived induced pluripotent stem cells (iPSCs) and their neural derivatives is becoming increasingly important in the study of neurodegenerative...
The use of patient-derived induced pluripotent stem cells (iPSCs) and their neural derivatives is becoming increasingly important in the study of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Lewy body dementia, amyotrophic lateral sclerosis, peripheral neuropathy, and so on. Increasingly, iPSC-derived neurons also reveal key pathways and signaling defects in psychiatric disorders such as autism spectrum disorders, schizophrenia, and bipolar disorder. With recent advances in CRISPR/Cas9-mediated genome editing technology, patient-derived iPSCs with disease-causing mutations can be corrected into "isogenic control lines," and these can be differentiated into neural derivatives with identical genetic background. This provides an opportunity for in vitro disease modeling to unravel disease mechanisms and a platform to facilitate drug discovery. In this chapter, we provide details of the differentiation protocols to reliably derive four currently relevant neuronal subtypes, i.e., cortical neurons, midbrain dopaminergic neurons, spinal motor neurons, and sensory neurons.
Topics: Cell Differentiation; Dopaminergic Neurons; Humans; Induced Pluripotent Stem Cells; Pluripotent Stem Cells; Sensory Receptor Cells
PubMed: 33959917
DOI: 10.1007/7651_2021_399 -
Military Medical Research Nov 2020Generation of neurons is essential in cell replacement therapy for neurodegenerative disorders like Parkinson's disease. Several studies have reported the generation of...
BACKGROUND
Generation of neurons is essential in cell replacement therapy for neurodegenerative disorders like Parkinson's disease. Several studies have reported the generation of dopaminergic (DA) neurons from mouse and human fibroblasts by ectopic expression of transcription factors, in which genetic manipulation is associated with potential risks.
METHODS
The small molecules and protein factors were selected based on their function to directly induce human fetal lung IMR-90 fibroblasts into DA neuron-like cells. Microscopical, immunocytochemical, and RT-qPCR analyses were used to characterize the morphology, phenotype, and gene expression features of the induced cells. The whole-cell patch-clamp recordings were exploited to measure the electrophysiological properties.
RESULTS
Human IMR-90 fibroblasts were rapidly converted into DA neuron-like cells after the chemical induction using small molecules and protein factors, with a yield of approximately 95% positive TUJ1-positive cells. The induced DA neuron-like cells were immunopositive for pan-neuronal markers MAP2, NEUN, and Synapsin 1 and DA markers TH, DDC, DAT, and NURR1. The chemical induction process did not involve a neural progenitor/stem cell intermediate stage. The induced neurons could fire single action potentials, which reflected partially the electrophysiological properties of neurons.
CONCLUSION
We developed a chemical cocktail of small molecules and protein factors to convert human fibroblasts into DA neuron-like cells without passing through a neural progenitor/stem cell intermediate stage. The induced DA neuron-like cells from human fibroblasts might provide a cellular source for cell-based therapy of Parkinson's disease in the future.
Topics: Dopaminergic Neurons; Fibroblasts; Furans; Gene Expression; Humans
PubMed: 33129359
DOI: 10.1186/s40779-020-00284-2 -
Scientific Reports Apr 2016Human pluripotent stem cells provide a powerful human-genome based system for modeling human diseases in vitro and for potentially identifying novel treatments. Directed...
Human pluripotent stem cells provide a powerful human-genome based system for modeling human diseases in vitro and for potentially identifying novel treatments. Directed differentiation of pluripotent stem cells produces many specific cell types including dopaminergic neurons. Here, we generated a genetic reporter assay in pluripotent stem cells using newly-developed genome editing technologies in order to monitor differentiation efficiency and compare dopaminergic neuron survival under different conditions. We show that insertion of a luciferase reporter gene into the endogenous tyrosine hydroxylase (TH) locus enables rapid and easy quantification of dopaminergic neurons in cell culture throughout the entire differentiation process. Moreover, we demonstrate that the cellular assay is effective in assessing neuron response to different cytotoxic chemicals and is able to be scaled for high throughput applications. These results suggest that stem cell-derived terminal cell types can provide an alternative to traditional immortal cell lines or primary cells as a quantitative cellular model for toxin evaluation and drug discovery.
Topics: Cell Differentiation; Cells, Cultured; Cytological Techniques; Cytotoxins; Dopaminergic Neurons; Gene Editing; Genes, Reporter; Genetic Loci; High-Throughput Screening Assays; Humans; Luciferases; Pluripotent Stem Cells
PubMed: 27121904
DOI: 10.1038/srep25181 -
Autophagy Sep 2017The molecular basis of chronic morphine exposure remains unknown. In this study, we hypothesized that macroautophagy/autophagy of dopaminergic neurons would mediate the...
The molecular basis of chronic morphine exposure remains unknown. In this study, we hypothesized that macroautophagy/autophagy of dopaminergic neurons would mediate the alterations of neuronal dendritic morphology and behavioral responses induced by morphine. Chronic morphine exposure caused Atg5 (autophagy-related 5)- and Atg7 (autophagy-related 7)-dependent and dopaminergic neuron-specific autophagy resulting in decreased neuron dendritic spines and the onset of addictive behaviors. In cultured primary midbrain neurons, morphine treatment significantly reduced total dendritic length and complexity, and this effect could be reversed by knockdown of Atg5 or Atg7. Mice deficient for Atg5 or Atg7 specifically in the dopaminergic neurons were less sensitive to developing a morphine reward response, behavioral sensitization, analgesic tolerance and physical dependence compared to wild-type mice. Taken together, our findings suggested that the Atg5- and Atg7-dependent autophagy of dopaminergic neurons contributed to cellular and behavioral responses to morphine and may have implications for the future treatment of drug addiction.
Topics: Animals; Autophagy; Autophagy-Related Protein 5; Autophagy-Related Protein 7; Behavior, Animal; Cell Shape; Dopaminergic Neurons; Gene Knockdown Techniques; Mesencephalon; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; Morphine; Nociception; PC12 Cells; Rats
PubMed: 28722508
DOI: 10.1080/15548627.2017.1332549 -
Cells Dec 2023Advances in stem cell technologies open up new avenues for modelling development and diseases. The success of these pursuits, however, relies on the use of cells most...
Single-Cell Transcriptomics and In Vitro Lineage Tracing Reveals Differential Susceptibility of Human iPSC-Derived Midbrain Dopaminergic Neurons in a Cellular Model of Parkinson's Disease.
Advances in stem cell technologies open up new avenues for modelling development and diseases. The success of these pursuits, however, relies on the use of cells most relevant to those targeted by the disease of interest, for example, midbrain dopaminergic neurons for Parkinson's disease. In the present study, we report the generation of a human induced pluripotent stem cell (iPSC) line capable of purifying and tracing nascent midbrain dopaminergic progenitors and their differentiated progeny via the expression of a Blue Fluorescent Protein (BFP). This was achieved by CRISPR/Cas9-assisted knock-in of BFP and Cre into the safe harbour locus AAVS1 and an early midbrain dopaminergic lineage marker gene LMX1A, respectively. Immunocytochemical analysis and single-cell RNA sequencing of iPSC-derived neural cultures confirm developmental recapitulation of the human fetal midbrain and high-quality midbrain cells. By modelling Parkinson's disease-related drug toxicity using 1-Methyl-4-phenylpyridinium (MPP), we showed a preferential reduction of BFP cells, a finding demonstrated independently by cell death assays and single-cell transcriptomic analysis of MPP treated neural cultures. Together, these results highlight the importance of disease-relevant cell types in stem cell modelling.
Topics: Humans; Induced Pluripotent Stem Cells; Parkinson Disease; Dopaminergic Neurons; Dopamine; Gene Expression Profiling; Mesencephalon
PubMed: 38132179
DOI: 10.3390/cells12242860