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Trends in Molecular Medicine Apr 2022Parkinson's disease (PD) is characterized by dopaminergic (DA) neuron loss and the formation of cytoplasmic protein inclusions. Although the exact pathogenesis of PD is... (Review)
Review
Parkinson's disease (PD) is characterized by dopaminergic (DA) neuron loss and the formation of cytoplasmic protein inclusions. Although the exact pathogenesis of PD is unknown, iron dyshomeostasis has been proposed as a potential contributing factor. Emerging evidence suggests that glial cell activation plays a pivotal role in ferroptosis and subsequent neurodegeneration. We review the association between iron deposition, glial activation, and neuronal death, and discuss whether and how ferroptosis affects α-synuclein aggregation and DA neuron loss. We examine the possible roles of different types of glia in mediating ferroptosis in neurons. Lastly, we review current PD clinical trials targeting iron homeostasis. Although clinical trials are already evaluating ferroptosis modulation in PD, much remains unknown about metal ion metabolism and regulation in PD pathogenesis.
Topics: Cell Death; Dopaminergic Neurons; Ferroptosis; Humans; Neuroglia; Parkinson Disease; alpha-Synuclein
PubMed: 35260343
DOI: 10.1016/j.molmed.2022.02.003 -
Cells Dec 2020Parkinson's disease (PD) is the second most common neurodegenerative disease. PD patients exhibit motor symptoms such as akinesia/bradykinesia, tremor, rigidity, and... (Review)
Review
Parkinson's disease (PD) is the second most common neurodegenerative disease. PD patients exhibit motor symptoms such as akinesia/bradykinesia, tremor, rigidity, and postural instability due to a loss of nigrostriatal dopaminergic neurons. Although the pathogenesis in sporadic PD remains unknown, there is a consensus on the involvement of non-neuronal cells in the progression of PD pathology. Astrocytes are the most numerous glial cells in the central nervous system. Normally, astrocytes protect neurons by releasing neurotrophic factors, producing antioxidants, and disposing of neuronal waste products. However, in pathological situations, astrocytes are known to produce inflammatory cytokines. In addition, various studies have reported that astrocyte dysfunction also leads to neurodegeneration in PD. In this article, we summarize the interaction of astrocytes and dopaminergic neurons, review the pathogenic role of astrocytes in PD, and discuss therapeutic strategies for the prevention of dopaminergic neurodegeneration. This review highlights neuron-astrocyte interaction as a target for the development of disease-modifying drugs for PD in the future.
Topics: Animals; Antioxidants; Astrocytes; Disease Progression; Dopamine; Dopaminergic Neurons; Humans; Inflammation; Mitochondria; Nerve Degeneration; Neuroglia; Neurons; Neuroprotection; Oxidative Stress; Parkinson Disease; Signal Transduction; alpha-Synuclein
PubMed: 33297340
DOI: 10.3390/cells9122623 -
Brain Research Bulletin Jul 2023Impairments in systematic and regional glucose metabolism exist in patients with Parkinson's disease (PD) at every stage of the disease course, and such impairments are... (Review)
Review
Impairments in systematic and regional glucose metabolism exist in patients with Parkinson's disease (PD) at every stage of the disease course, and such impairments are associated with the incidence, progression, and special phenotypes of PD, which affect each physiological process of glucose metabolism including glucose uptake, glycolysis, tricarboxylic acid cycle, oxidative phosphorylation, and pentose phosphate shunt pathway. These impairments may be attributed to various mechanisms, such as insulin resistance, oxidative stress, abnormal glycated modification, blood-brain-barrier dysfunction, and hyperglycemia-induced damages. These mechanisms could subsequently cause excessive methylglyoxal and reactive oxygen species production, neuroinflammation, abnormal aggregation of protein, mitochondrial dysfunction, and decreased dopamine, and finally result in energy supply insufficiency, neurotransmitter dysregulation, aggregation and phosphorylation of α-synuclein, and dopaminergic neuron loss. This review discusses the glucose metabolism impairment in PD and its pathophysiological mechanisms, and briefly summarized the currently-available therapies targeting glucose metabolism impairment in PD, including glucagon-likepeptide-1 (GLP-1) receptor agonists and dual GLP-1/gastric inhibitory peptide receptor agonists, metformin, and thiazoledinediones.
Topics: Humans; Parkinson Disease; Hyperglycemia; Glycolysis; Dopamine; Glucose; Glucagon-Like Peptide 1; Dopaminergic Neurons
PubMed: 37210012
DOI: 10.1016/j.brainresbull.2023.110672 -
Nature Communications Mar 2020Microglia maintain brain homeostasis by removing neuron-derived components such as myelin and cell debris. The evidence linking microglia to neurodegenerative diseases...
Microglia maintain brain homeostasis by removing neuron-derived components such as myelin and cell debris. The evidence linking microglia to neurodegenerative diseases is growing; however, the precise mechanisms remain poorly understood. Herein, we report a neuroprotective role for microglia in the clearance of neuron-released α-synuclein. Neuronal α-synuclein activates microglia, which in turn engulf α-synuclein into autophagosomes for degradation via selective autophagy (termed synucleinphagy). Synucleinphagy requires the presence of microglial Toll-like receptor 4 (TLR4), which induces transcriptional upregulation of p62/SQSTM1 through the NF-κB signaling pathway. Induction of p62, an autophagy receptor, is necessary for the formation of α-synuclein/ubiquitin-positive puncta that are degraded by autophagy. Finally, disruption of microglial autophagy in mice expressing human α-synuclein promotes the accumulation of misfolded α-synuclein and causes midbrain dopaminergic neuron degeneration. Our study thus identifies a neuroprotective function of microglia in the clearance of α-synuclein via TLR4-NF-κB-p62 mediated synucleinphagy.
Topics: Animals; Autoantigens; Autophagy; Brain; Disease Models, Animal; Dopaminergic Neurons; Female; HEK293 Cells; Humans; Mesencephalon; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; NF-kappa B; Neurodegenerative Diseases; Signal Transduction; Toll-Like Receptor 4; alpha-Synuclein
PubMed: 32170061
DOI: 10.1038/s41467-020-15119-w -
Seminars in Immunopathology Sep 2022Parkinson's disease (PD) is the second most common neurodegenerative disorder which affects 6.1 million people worldwide. The neuropathological hallmarks include the... (Review)
Review
Parkinson's disease (PD) is the second most common neurodegenerative disorder which affects 6.1 million people worldwide. The neuropathological hallmarks include the loss of dopaminergic neurons in the substantia nigra, the presence of Lewy bodies and Lewy neurites caused by α-synuclein aggregation, and neuroinflammation in the brain. The prodromal phase happens years before the onset of PD during which time many patients show gastro-intestinal symptoms. These symptoms are in support of Braak's theory and model where pathological α-synuclein propagates from the gut to the brain. Importantly, immune responses play a determinant role in the pathogenesis of Parkinson's disease. The innate immune responses triggered by microglia can cause neuronal death and disease progression. In addition, T cells infiltrate into the brains of PD patients and become involved in the adaptive immune responses. Interestingly, α-synuclein is associated with both innate and adaptive immune responses by directly interacting with microglia and T cells. Here, we give a detailed review of the immunobiology of Parkinson's disease, focusing on the role α-synuclein in the gut-brain axis hypothesis, the innate and adaptive immune responses involved in the disease, and current treatments.
Topics: Brain; Dopaminergic Neurons; Humans; Neurodegenerative Diseases; Parkinson Disease; alpha-Synuclein
PubMed: 35674826
DOI: 10.1007/s00281-022-00947-3 -
Brain : a Journal of Neurology Apr 2022Idiopathic Parkinson's disease is characterized by a progressive loss of dopaminergic neurons, but the exact disease aetiology remains largely unknown. To date,...
Idiopathic Parkinson's disease is characterized by a progressive loss of dopaminergic neurons, but the exact disease aetiology remains largely unknown. To date, Parkinson's disease research has mainly focused on nigral dopaminergic neurons, although recent studies suggest disease-related changes also in non-neuronal cells and in midbrain regions beyond the substantia nigra. While there is some evidence for glial involvement in Parkinson's disease, the molecular mechanisms remain poorly understood. The aim of this study was to characterize the contribution of all cell types of the midbrain to Parkinson's disease pathology by single-nuclei RNA sequencing and to assess the cell type-specific risk for Parkinson's disease using the latest genome-wide association study. We profiled >41 000 single-nuclei transcriptomes of post-mortem midbrain from six idiopathic Parkinson's disease patients and five age-/sex-matched controls. To validate our findings in a spatial context, we utilized immunolabelling of the same tissues. Moreover, we analysed Parkinson's disease-associated risk enrichment in genes with cell type-specific expression patterns. We discovered a neuronal cell cluster characterized by CADPS2 overexpression and low TH levels, which was exclusively present in idiopathic Parkinson's disease midbrains. Validation analyses in laser-microdissected neurons suggest that this cluster represents dysfunctional dopaminergic neurons. With regard to glial cells, we observed an increase in nigral microglia in Parkinson's disease patients. Moreover, nigral idiopathic Parkinson's disease microglia were more amoeboid, indicating an activated state. We also discovered a reduction in idiopathic Parkinson's disease oligodendrocyte numbers with the remaining cells being characterized by a stress-induced upregulation of S100B. Parkinson's disease risk variants were associated with glia- and neuron-specific gene expression patterns in idiopathic Parkinson's disease cases. Furthermore, astrocytes and microglia presented idiopathic Parkinson's disease-specific cell proliferation and dysregulation of genes related to unfolded protein response and cytokine signalling. While reactive patient astrocytes showed CD44 overexpression, idiopathic Parkinson's disease microglia revealed a pro-inflammatory trajectory characterized by elevated levels of IL1B, GPNMB and HSP90AA1. Taken together, we generated the first single-nuclei RNA sequencing dataset from the idiopathic Parkinson's disease midbrain, which highlights a disease-specific neuronal cell cluster as well as 'pan-glial' activation as a central mechanism in the pathology of the movement disorder. This finding warrants further research into inflammatory signalling and immunomodulatory treatments in Parkinson's disease.
Topics: Dopaminergic Neurons; Genome-Wide Association Study; Humans; Membrane Glycoproteins; Mesencephalon; Microglia; Parkinson Disease; Substantia Nigra
PubMed: 34919646
DOI: 10.1093/brain/awab446 -
Current Opinion in Neurobiology Apr 2021Dopamine neurons have been intensely studied for their roles in reinforcement learning. A dominant theory of how these neurons contribute to learning is through the... (Review)
Review
Dopamine neurons have been intensely studied for their roles in reinforcement learning. A dominant theory of how these neurons contribute to learning is through the encoding of a reward prediction error (RPE) signal. Recent advances in dopamine research have added nuance to RPE theory by incorporating the ideas of sensory prediction error, distributional encoding, and belief states. Further nuance is likely to be added shortly by convergent lines of research on dopamine neuron diversity. Finally, a major challenge is to reconcile RPE theory with other current theories of dopamine function to account for dopamine's role in movement, motivation, and goal-directed planning.
Topics: Dopamine; Dopaminergic Neurons; Motivation; Reinforcement, Psychology; Reward
PubMed: 33197709
DOI: 10.1016/j.conb.2020.10.012 -
Nature Communications May 2023Parkinson's disease (PD) is a complex neurodegenerative disease with etiology rooted in genetic vulnerability and environmental factors. Here we combine quantitative...
Parkinson's disease (PD) is a complex neurodegenerative disease with etiology rooted in genetic vulnerability and environmental factors. Here we combine quantitative epidemiologic study of pesticide exposures and PD with toxicity screening in dopaminergic neurons derived from PD patient induced pluripotent stem cells (iPSCs) to identify Parkinson's-relevant pesticides. Agricultural records enable investigation of 288 specific pesticides and PD risk in a comprehensive, pesticide-wide association study. We associate long-term exposure to 53 pesticides with PD and identify co-exposure profiles. We then employ a live-cell imaging screening paradigm exposing dopaminergic neurons to 39 PD-associated pesticides. We find that 10 pesticides are directly toxic to these neurons. Further, we analyze pesticides typically used in combinations in cotton farming, demonstrating that co-exposures result in greater toxicity than any single pesticide. We find trifluralin is a driver of toxicity to dopaminergic neurons and leads to mitochondrial dysfunction. Our paradigm may prove useful to mechanistically dissect pesticide exposures implicated in PD risk and guide agricultural policy.
Topics: Humans; Pesticides; Parkinson Disease; Induced Pluripotent Stem Cells; Neurodegenerative Diseases; Dopaminergic Neurons
PubMed: 37193692
DOI: 10.1038/s41467-023-38215-z -
Oxidative Medicine and Cellular... 2022Ferroptosis, a novel form of regulated cell death, is caused by accumulation of lipid peroxides and excessive iron deposition. This process has been linked to the death...
Ferroptosis, a novel form of regulated cell death, is caused by accumulation of lipid peroxides and excessive iron deposition. This process has been linked to the death of dopaminergic neurons in substantia nigra compacta (SNc) of Parkinson's disease (PD) patients. Quercetin (QCT), a natural flavonoid, has multiple pharmacological activities. However, it has not been established whether QCT can protect against dopaminergic neuron death by inhibiting ferroptosis. In this study, we investigated the potential antiferroptotic effects of QCT in cellular models established using specific ferroptosis inducers (Erastin and RSL-3) and MPP. The effects were also explored using MPTP-induced PD mouse models. The cell counting kit-8 (CCK-8) assay was performed to assess cell viability. Variations in mitochondrial morphology were evaluated by transmission electron microscopy (TEM) while the mitochondrial membrane potential, mass, and ROS were measured by fluorescent probes. Lipid peroxidation levels were assayed through measurement of lipid ROS, MDA, GSH, and SOD levels. The effects of QCT on MPTP-induced behavioral disorders were examined by rotarod and open field tests. and , QCT significantly inhibited ferroptosis by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) protein. Additionally, QCT ameliorated motor behavioral impairments and protected against the loss of dopaminergic neurons in MPTP-induced PD models. Interestingly, Nrf2 knockdown alleviated the protective effects of QCT against ferroptosis. In conclusion, these results demonstrate that ferroptosis is involved in MPP/MPTP-induced PD, and QCT inhibits ferroptosis by activating the Nrf2 protein. Therefore, QCT is a potential agent for preventing the loss of dopaminergic neurons by targeting ferroptosis.
Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Dopamine; Dopaminergic Neurons; Ferroptosis; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Parkinson Disease; Piperidines; Pyrazoles; Quercetin; Reactive Oxygen Species
PubMed: 36105483
DOI: 10.1155/2022/7769355 -
Cell Stem Cell Feb 2024COVID-19 patients commonly present with signs of central nervous system and/or peripheral nervous system dysfunction. Here, we show that midbrain dopamine (DA) neurons...
COVID-19 patients commonly present with signs of central nervous system and/or peripheral nervous system dysfunction. Here, we show that midbrain dopamine (DA) neurons derived from human pluripotent stem cells (hPSCs) are selectively susceptible and permissive to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. SARS-CoV-2 infection of DA neurons triggers an inflammatory and cellular senescence response. High-throughput screening in hPSC-derived DA neurons identified several FDA-approved drugs that can rescue the cellular senescence phenotype by preventing SARS-CoV-2 infection. We also identified the inflammatory and cellular senescence signature and low levels of SARS-CoV-2 transcripts in human substantia nigra tissue of COVID-19 patients. Furthermore, we observed reduced numbers of neuromelanin+ and tyrosine-hydroxylase (TH)+ DA neurons and fibers in a cohort of severe COVID-19 patients. Our findings demonstrate that hPSC-derived DA neurons are susceptible to SARS-CoV-2, identify candidate neuroprotective drugs for COVID-19 patients, and suggest the need for careful, long-term monitoring of neurological problems in COVID-19 patients.
Topics: Humans; COVID-19; SARS-CoV-2; Dopaminergic Neurons; Central Nervous System; Pluripotent Stem Cells
PubMed: 38237586
DOI: 10.1016/j.stem.2023.12.012