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Neurosciences (Riyadh, Saudi Arabia) Jan 2023Parkinson's disease (PD) is a progressive widespread neurodegenerative disorder affecting the brain. It is characterized by dopaminergic neuron degeneration in the... (Review)
Review
Parkinson's disease (PD) is a progressive widespread neurodegenerative disorder affecting the brain. It is characterized by dopaminergic neuron degeneration in the substantia nigra pars compacta (SNpc). Current therapeutic options ease the symptoms of PD; however, they have multiple undesirable effects and do not slow the disease progression. Exercise by itself has many positive impacts on general health. In this review, the positive impact of different forms of exercise were found to improve motor and non-motor symptoms in PD. Exercise effects is mediate by multiple mechanisms, including the upregulation of brain-derived neurotrophic factor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, and autophagy regulating proteins; and downregulates proinflammatory cytokines. In this review, the significance of exercise in PD, as well as in the prevention and maintenance of the disease was discussed. Many questions are left unanswered in this manuscript, including potential genetic factors underlying response to exercise. Therefore, further high-quality studies on humans are needed.
Topics: Humans; Animals; Parkinson Disease; Dopamine; Exercise; Dopaminergic Neurons; Disease Models, Animal
PubMed: 36617448
DOI: 10.17712/nsj.2023.1.20220105 -
Journal of Neurochemistry May 2023Dietary lipids, particularly omega-3 polyunsaturated fatty acids, are speculated to impact behaviors linked to the dopaminergic system, such as movement and control of...
Dietary lipids, particularly omega-3 polyunsaturated fatty acids, are speculated to impact behaviors linked to the dopaminergic system, such as movement and control of circadian rhythms. However, the ability to draw a direct link between dopaminergic omega-3 fatty acid metabolism and behavioral outcomes has been limited to the use of diet-based approaches, which are confounded by systemic effects. Here, neuronal lipid metabolism was targeted in a diet-independent manner by manipulation of long-chain acyl-CoA synthetase 6 (ACSL6) expression. ACSL6 performs the initial reaction for cellular fatty acid metabolism and prefers the omega-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA). The loss of Acsl6 in mice (Acsl6 ) depletes neuronal membranes of DHA content and results in phenotypes linked to dopaminergic control, such as hyperlocomotion, impaired short-term spatial memory, and imbalances in dopamine neurochemistry. To investigate the role of dopaminergic ACSL6 on these outcomes, a dopaminergic neuron-specific ACSL6 knockout mouse was generated (Acsl6 ). Acsl6 mice demonstrated hyperlocomotion and imbalances in striatal dopamine neurochemistry. Circadian rhythms of both the Acsl6 and the Acsl6 mice were similar to control mice under basal conditions. However, upon light entrainment, a mimetic of jet lag, both the complete knockout of ACSL6 and the dopaminergic-neuron-specific loss of ACSL6 resulted in a longer recovery to entrainment compared to control mice. In conclusion, these data demonstrate that ACSL6 in dopaminergic neurons alters dopamine metabolism and regulation of light entrainment suggesting that DHA metabolism mediated by ACSL6 plays a role in dopamine neuron biology.
Topics: Mice; Animals; Dopaminergic Neurons; Lipid Metabolism; Dopamine; Dietary Fats; Diet; Mice, Knockout; Docosahexaenoic Acids; Coenzyme A Ligases
PubMed: 36815399
DOI: 10.1111/jnc.15793 -
International Journal of Molecular... Feb 2018Mitochondria are important organelles in virtually all eukaryotic cells, and are involved in a wide range of physiological and pathophysiological processes. Besides the... (Review)
Review
Mitochondria are important organelles in virtually all eukaryotic cells, and are involved in a wide range of physiological and pathophysiological processes. Besides the generation of cellular energy in the form of adenosine triphosphate, mitochondria are also involved in calcium homeostasis, reactive oxygen species production and the activation of the intrinsic cell death pathway, thus determining cell survival and death. Mitochondrial abnormalities have been implicated in a wide range of disorders, including neurodegenerative disease such as Parkinson's disease (PD), and considered as a primary cause and central event responsible for the progressive loss of dopaminergic neurons in PD. Thus, reversion or attenuation of mitochondrial dysfunction should alleviate the severity or progression of the disease. The present review systematically summarizes the possible mechanisms associated with mitochondria‑mediated dopaminergic neuron damage in PD, in an attempt to elucidate the requirement for further studies for the development of effective PD treatments.
Topics: Calcium; Cell Death; Dopaminergic Neurons; Humans; Mitochondria; Parkinson Disease; Reactive Oxygen Species; Signal Transduction
PubMed: 29207041
DOI: 10.3892/ijmm.2017.3255 -
Molecular Psychiatry May 2023Dopaminergic neurons are critical to movement, mood, addiction, and stress. Current techniques for generating dopaminergic neurons from human induced pluripotent stem...
Dopaminergic neurons are critical to movement, mood, addiction, and stress. Current techniques for generating dopaminergic neurons from human induced pluripotent stem cells (hiPSCs) yield heterogenous cell populations with variable purity and inconsistent reproducibility between donors, hiPSC clones, and experiments. Here, we report the rapid (5 weeks) and efficient (~90%) induction of induced dopaminergic neurons (iDANs) through transient overexpression of lineage-promoting transcription factors combined with stringent selection across five donors. We observe maturation-dependent increase in dopamine synthesis and electrophysiological properties consistent with midbrain dopaminergic neuron identity, such as slow-rising after- hyperpolarization potentials, an action potential duration of ~3 ms, tonic sub-threshold oscillatory activity, and spontaneous burst firing at a frequency of ~1.0-1.75 Hz. Transcriptome analysis reveals robust expression of genes involved in fetal midbrain dopaminergic neuron identity. Specifically expressed genes in iDANs, as well as those from isogenic induced GABAergic and glutamatergic neurons, were enriched in loci conferring heritability for cannabis use disorder, schizophrenia, and bipolar disorder; however, each neuronal subtype demonstrated subtype-specific heritability enrichments in biologically relevant pathways, and iDANs alone were uniquely enriched in autism spectrum disorder risk loci. Therefore, iDANs provide a critical tool for modeling midbrain dopaminergic neuron development and dysfunction in psychiatric disease.
Topics: Humans; Dopaminergic Neurons; Autism Spectrum Disorder; Reproducibility of Results; Induced Pluripotent Stem Cells; Mesencephalon
PubMed: 34493831
DOI: 10.1038/s41380-021-01273-0 -
Neurotoxicology Jan 2024Caenorhabditis elegans (C. elegans) is an excellent model system to study neurodegenerative diseases, such as Parkinson's disease, as it enables analysis of both neuron...
Caenorhabditis elegans (C. elegans) is an excellent model system to study neurodegenerative diseases, such as Parkinson's disease, as it enables analysis of both neuron morphology and function in live animals. Multiple structural changes in neurons, such as cephalic dendrite morphological abnormalities, have been considered hallmarks of neurodegeneration in this model, but their relevance to changes in neuron function are not entirely clear. We sought to test whether hallmark morphological changes associated with chemically induced dopaminergic neuron degeneration, such as dendrite blebbing, breakage, and loss, are indicative of neuronal malfunction and result in changes in behavior. We adapted an established dopaminergic neuronal function assay by measuring paralysis in the presence of exogenous dopamine, which revealed clear differences between cat-2 dopamine deficient mutants, wildtype worms, and dat-1 dopamine abundant mutants. Next, we integrated an automated image processing algorithm and a microfluidic device to segregate worm populations by their cephalic dendrite morphologies. We show that nematodes with dopaminergic dendrite degeneration markers, such as blebbing or breakage, paralyze at higher rates in a dopamine solution, providing evidence that dopaminergic neurodegeneration morphologies are correlated with functional neuronal outputs.
Topics: Animals; Caenorhabditis elegans; Dopamine; Animals, Genetically Modified; Caenorhabditis elegans Proteins; Dopaminergic Neurons; Disease Models, Animal
PubMed: 38070655
DOI: 10.1016/j.neuro.2023.12.005 -
Food and Chemical Toxicology : An... Jun 2022Activated microglia play an active role in the pathogenesis of PD and paraquat (PQ) induces PD. The study was to understand the time relationship between microglial...
Activated microglia play an active role in the pathogenesis of PD and paraquat (PQ) induces PD. The study was to understand the time relationship between microglial activation and dopaminergic neuron loss in the substantia nigra (SN) of PQ-induced PD mice. Male C57BL/6 mice were injected intraperitoneally with PQ, twice a week for six weeks. Some mice underwent behavioral assessments each week and were sacrificed for SN tissues, in which histopathological analysis, dopaminergic neuron loss, microglial activation and phenotypic characteristics were evaluated. The results showed that motor retardation, coordination disorders and limb stiffness occurred four weeks after PQ exposure, as well as the degeneration and loss of dopaminergic neurons in the SN. Activated microglia and increased CD68 expression appeared two weeks after PQ exposure in time-dependent manners. Increased CD86 and decreased CD206 expression were observed four weeks after PQ exposure, accompanied by increased TNF-α and IL-6 levels and decreased IL-10 and TGF-β levels. These results indicate that PQ can activate microglia in vivo, and microglial activation precedes neuronal loss in the SN. Activated microglia are characterized by mixed M1/M2 polarization in the early stage and M1 polarization in the late stage of PQ-induced PD development.
Topics: Animals; Dopamine; Dopaminergic Neurons; Male; Mice; Mice, Inbred C57BL; Microglia; Nerve Degeneration; Paraquat; Parkinson Disease; Substantia Nigra
PubMed: 35430334
DOI: 10.1016/j.fct.2022.113018 -
Cell Reports Oct 2023Dopaminergic neurons (DANs) drive associative learning to update the value of sensory cues, but their contribution to the assessment of sensory values outside the...
Dopaminergic neurons (DANs) drive associative learning to update the value of sensory cues, but their contribution to the assessment of sensory values outside the context of association remains largely unexplored. Here, we show in Drosophila that DANs in the mushroom body encode the innate value of odors and constantly update the current value by inducing plasticity during olfactory maneuver. Our connectome-based network model linking all the way from the olfactory neurons to DANs reproduces the characteristics of DAN responses, proposing a concrete circuit mechanism for computation. Downstream of DANs, odors alone induce value- and dopamine-dependent changes in the activity of mushroom body output neurons, which store the current value of odors. Consistent with this neural plasticity, specific sets of DANs bidirectionally modulate flies' steering in a virtual olfactory environment. Thus, the DAN circuit known for discrete, associative learning also continuously updates odor values in a nonassociative manner.
Topics: Animals; Dopaminergic Neurons; Smell; Drosophila; Odorants; Dopamine; Mushroom Bodies; Drosophila melanogaster
PubMed: 37757823
DOI: 10.1016/j.celrep.2023.113122 -
Journal of Cellular and Molecular... Sep 2021N6-Methyladenosine (m6A) is the most prevalent internal modification in messenger RNAs (mRNAs) of eukaryotes and plays a vital role in post-transcriptional regulation....
N6-Methyladenosine (m6A) is the most prevalent internal modification in messenger RNAs (mRNAs) of eukaryotes and plays a vital role in post-transcriptional regulation. Recent studies demonstrated that m6A is essential for the normal function of the central nervous system (CNS), and the deregulation of m6A leads to a series of CNS diseases. However, the functional consequences of m6A deficiency within the dopaminergic neurons of adult brain are elusive. To evaluate the necessity of m6A in dopaminergic neuron functions, we conditionally deleted Mettl14, one of the most important part of m6A methyltransferase complexes, in the substantia nigra (SN) region enriched with dopaminergic neurons. By using rotarod test, pole test, open-field test and elevated plus maze, we found that the deletion of Mettl14 in the SN region induces impaired motor function and locomotor activity. Further molecular analysis revealed that Mettl14 deletion significantly reduced the total level of m6A in the mRNA isolated from SN region. Tyrosine hydroxylase (TH), an essential enzyme for dopamine synthesis, was also down-regulated upon Mettl14 deletion, while the activation of microglia and astrocyte was enhanced. Moreover, the expression of three essential transcription factors in the regulation of TH including Nurr1, Pitx3 and En1, with abundant m6A-binding sites on their RNA 3'-untranslated regions (UTR), was significantly decreased upon Mettl14 deletion in SN. Our finding first confirmed the significance of m6A in maintaining normal dopaminergic function in the SN of adult mouse.
Topics: Animals; Central Nervous System Diseases; Dopaminergic Neurons; Methyltransferases; Mice; Mice, Inbred C57BL; Substantia Nigra
PubMed: 34288397
DOI: 10.1111/jcmm.16740 -
Brain Research Apr 2022Cuprizone (CPZ) is a copper-chelator and toxic to mitochondria. Recent studies have shown oligodendrocyte (OL) loss and demyelination along with dopamine (DA) increase...
Cuprizone (CPZ) is a copper-chelator and toxic to mitochondria. Recent studies have shown oligodendrocyte (OL) loss and demyelination along with dopamine (DA) increase and behavioral abnormalities in CPZ-exposed mice, demonstrating its application in schizophrenia research. This study examined effects of CPZ exposure on autonomous behavior and dopaminergic neurotransmission in larval zebra fish. CPZ exposure was found to reduce the swimming velocity of zebra fish thus decreased swimming distance during day and night time. Moreover, the treatment induced a movement response of zebra fish larvae reacting to light-on/off switch featured by swimming velocity increase and decrease during the first and second half of the light-on/off phase, respectively. But, it abolished responses of zebra fish to sound-on/off seen in Control group. HPLC analysis showed elevated DA levels in the zebra fish, no change in NE and 5-HT levels. Transcriptome analysis reported changes in gene expression related to dopaminergic synapse and oxidative phosphorylation in CPZ-exposed larvae relative to Control group. Of the gene expression changes, up-regulation of drd2a, drd2b, drd4a and drd4rs was confirmed by RT-PCR, although no difference existed between Control and CPZ groups in dopaminergic neuron numbers. These results demonstrated dopaminergic hyperactivity and locomotor deficit in CPZ-exposed zebra fish larvae, encouraging further application of this model in exploring neurotoxic effects of CPZ on mitochondria and dopaminergic neurotransmission in zebra fish.
Topics: Animals; Behavior, Animal; Cuprizone; Disease Models, Animal; Dopamine; Dopaminergic Neurons; Motor Activity; Synaptic Transmission; Zebrafish
PubMed: 35085574
DOI: 10.1016/j.brainres.2022.147802 -
Cell Transplantation Sep 2017Cell therapy for Parkinson's disease (PD) began in 1979 with the transplantation of fetal rat dopamine-containing neurons that improved motor abnormalities in the PD rat... (Review)
Review
Cell therapy for Parkinson's disease (PD) began in 1979 with the transplantation of fetal rat dopamine-containing neurons that improved motor abnormalities in the PD rat model with good survival of grafts and axonal outgrowth. Thirty years have passed since the 2 clinical trials using cell transplantation for PD patients were first reported. Recently, cell therapy is expected to develop as a realistic treatment option for PD patients owing to the advancement of biotechnology represented by pluripotent stem cells. Medication using levodopa, surgery including deep brain stimulation, and rehabilitation have all been established as current therapeutic strategies. Strong therapeutic effects have been demonstrated by these treatment methods, but they have been unable to stop the progression of the disease. Fortunately, cell therapy might be a key for true neurorestoration. This review article describes the historical development of cell therapy for PD, the current status of cell therapy, and the future direction of this treatment method.
Topics: Animals; Cell Differentiation; Cell- and Tissue-Based Therapy; Dopaminergic Neurons; Humans; Parkinson Disease; Stem Cell Transplantation
PubMed: 29113472
DOI: 10.1177/0963689717735411