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International Journal of Molecular... Jul 2023Dopamine is a well-known neurotransmitter due to its involvement in Parkinson's disease (PD). Dopamine is not only involved in PD but also controls multiple mental and... (Review)
Review
Dopamine is a well-known neurotransmitter due to its involvement in Parkinson's disease (PD). Dopamine is not only involved in PD but also controls multiple mental and physical activities, such as the pleasure of food, friends and loved ones, music, art, mood, cognition, motivation, fear, affective disorders, addiction, attention deficit disorder, depression, and schizophrenia. Dopaminergic neurons (DOPAn) are susceptible to stressors, and inflammation is a recognized risk for neuronal malfunctioning and cell death in major neurodegenerative diseases. Less is known for non-neurodegenerative conditions. Among the endogenous defenses, bilirubin, a heme metabolite, has been shown to possess important anti-inflammatory activity and, most importantly, to prevent DOPAn demise in an ex vivo model of PD by acting on the tumor necrosis factor-alpha (TNFα). This review summarizes the evidence linking DOPAn, inflammation (when possible, specifically TNFα), and bilirubin as an anti-inflammatory in order to understand what is known, the gaps that need filling, and the hypotheses of anti-inflammatory strategies to preserve dopamine homeostasis with bilirubin included.
Topics: Humans; Dopamine; Tumor Necrosis Factor-alpha; Bilirubin; Brain; Parkinson Disease; Inflammation; Dopaminergic Neurons; Anti-Inflammatory Agents
PubMed: 37511235
DOI: 10.3390/ijms241411478 -
Neuron Nov 2023Enteric symptoms are hallmarks of prodromal Parkinson's disease (PD) that appear decades before the onset of motor symptoms and diagnosis. PD patients possess...
Enteric symptoms are hallmarks of prodromal Parkinson's disease (PD) that appear decades before the onset of motor symptoms and diagnosis. PD patients possess circulating T cells that recognize specific α-synuclein (α-syn)-derived epitopes. One epitope, α-syn, binds with strong affinity to the HLA-DRB115:01 allele implicated in autoimmune diseases. We report that α-syn immunization in a mouse expressing human HLA-DRB115:01 triggers intestinal inflammation, leading to loss of enteric neurons, damaged enteric dopaminergic neurons, constipation, and weight loss. α-Syn immunization activates innate and adaptive immune gene signatures in the gut and induces changes in the CD4 T1/T17 transcriptome that resemble tissue-resident memory (T) cells found in mucosal barriers during inflammation. Depletion of CD4, but not CD8, T cells partially rescues enteric neurodegeneration. Therefore, interaction of α-syn and HLA-DRB115:0 is critical for gut inflammation and CD4 T cell-mediated loss of enteric neurons in humanized mice, suggesting mechanisms that may underlie prodromal enteric PD.
Topics: Mice; Humans; Animals; Parkinson Disease; alpha-Synuclein; HLA-DRB1 Chains; Epitopes; Dopaminergic Neurons; Inflammation
PubMed: 37597517
DOI: 10.1016/j.neuron.2023.07.015 -
Molecular Neurodegeneration Dec 2023Parkinson's disease (PD), one of the most devastating neurodegenerative brain disorders, is characterized by the progressive loss of dopaminergic neurons in the...
Parkinson's disease (PD), one of the most devastating neurodegenerative brain disorders, is characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) and deposits of α-synuclein aggregates. Currently, pharmacological interventions for PD remain inadequate. The cell necroptosis executor protein MLKL (Mixed-lineage kinase domain-like) is involved in various diseases, including inflammatory bowel disease and neurodegenerative diseases; however, its precise role in PD remains unclear. Here, we investigated the neuroprotective role of MLKL inhibition or ablation against primary neuronal cells and human iPSC-derived midbrain organoids induced by toxic α-Synuclein preformed fibrils (PFFs). Using a mouse model (Tg-Mlkl) generated by crossbreeding the SNCA A53T synuclein transgenic mice with MLKL knockout (KO)mice, we assessed the impact of MLKL deficiency on the progression of Parkinsonian traits. Our findings demonstrate that Tg-Mlkl mice exhibited a significant improvement in motor symptoms and reduced phosphorylated α-synuclein expression compared to the classic A53T transgenic mice. Furthermore, MLKL deficiency alleviated tyrosine hydroxylase (TH)-positive neuron loss and attenuated neuroinflammation by inhibiting the activation of microglia and astrocytes. Single-cell RNA-seq (scRNA-seq) analysis of the SN of Tg-Mlkl mice revealed a unique cell type-specific transcriptome profile, including downregulated prostaglandin D synthase (PTGDS) expression, indicating reduced microglial cells and dampened neuron death. Thus, MLKL represents a critical therapeutic target for reducing neuroinflammation and preventing motor deficits in PD.
Topics: Animals; Humans; Mice; alpha-Synuclein; Disease Models, Animal; Dopaminergic Neurons; Mice, Knockout; Mice, Transgenic; Neuroinflammatory Diseases; Parkinson Disease; Protein Kinases; Substantia Nigra
PubMed: 38041169
DOI: 10.1186/s13024-023-00686-5 -
Nature Jul 2023Fast-acting neurotransmitters and slow, modulatory neuropeptides are co-released from neurons in the central nervous system, albeit from distinct synaptic vesicles. The...
Fast-acting neurotransmitters and slow, modulatory neuropeptides are co-released from neurons in the central nervous system, albeit from distinct synaptic vesicles. The mechanisms of how co-released neurotransmitters and neuropeptides that have opposing actions-for example, stimulatory versus inhibitory-work together to exert control of neural circuit output remain unclear. This has been difficult to resolve owing to the inability to selectively isolate these signalling pathways in a cell- and circuit-specific manner. Here we developed a genetic-based anatomical disconnect procedure that utilizes distinct DNA recombinases to independently facilitate CRISPR-Cas9 mutagenesis of neurotransmitter- and neuropeptide-related genes in distinct cell types in two different brain regions simultaneously. We demonstrate that neurons within the lateral hypothalamus that produce the stimulatory neuropeptide neurotensin and the inhibitory neurotransmitter GABA (γ-aminobutyric acid) utilize these signals to coordinately activate dopamine-producing neurons of the ventral tegmental area. We show that GABA release from lateral hypothalamus neurotensin neurons inhibits GABA neurons within the ventral tegmental area, disinhibiting dopamine neurons and causing a rapid rise in calcium, whereas neurotensin directly generates a slow inactivating calcium signal in dopamine neurons that is dependent on the expression of neurotensin receptor 1 (Ntsr1). We further show that these two signals work together to regulate dopamine neuron responses to maximize behavioural responding. Thus, a neurotransmitter and a neuropeptide with opposing signals can act on distinct timescales through different cell types to enhance circuit output and optimize behaviour.
Topics: Brain; Calcium; CRISPR-Cas Systems; Dopamine; Dopaminergic Neurons; GABAergic Neurons; gamma-Aminobutyric Acid; Gene Editing; Hypothalamic Area, Lateral; Neural Pathways; Neurotensin; Neurotransmitter Agents; Receptors, Neurotensin; Signal Transduction; Ventral Tegmental Area
PubMed: 37380765
DOI: 10.1038/s41586-023-06246-7 -
ACS Nano Oct 2023Parkinson's disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopamine (DA) neurons in the midbrain substantia nigra pars compacta...
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopamine (DA) neurons in the midbrain substantia nigra pars compacta (SNpc). While existing therapeutic strategies can alleviate PD symptoms, they cannot inhibit DA neuron loss. Herein, a tailor-made human serum albumin (HSA)-based selenium nanosystem (HSA/Se nanoparticles, HSA/Se NPs) to treat PD that can overcome the intestinal epithelial barrier (IEB) and blood-brain barrier (BBB) is described. HSA, a transporter for drug delivery, has superior biological characteristics that make it an ideal potential drug delivery substance. Findings reveal that HSA/Se NPs have lower toxicity and higher efficacy than other selenium species and the ability to overcome the IEB and BBB to enrich DA neurons, which then protect MN9D cells from MPP-induced neurotoxicity and ameliorate both behavioral deficits and DA neuronal death in MPTP-model mice. Thus, a therapeutic drug delivery system composed of orally gavaged HSA/Se NPs for the treatment of PD is described.
Topics: Humans; Mice; Animals; Parkinson Disease; Selenium; Dopaminergic Neurons; Nanoparticles; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 37807265
DOI: 10.1021/acsnano.3c05011 -
Nature Neuroscience Sep 2023Fluctuations in reproductive hormone levels are associated with mood disruptions in women, such as in postpartum and perimenopausal depression. However, the neural...
Fluctuations in reproductive hormone levels are associated with mood disruptions in women, such as in postpartum and perimenopausal depression. However, the neural circuit mechanisms remain unclear. Here we report that medial preoptic area (MPOA) GABAergic neurons mediate multifaceted depressive-like behaviors in female mice after ovarian hormone withdrawal (HW), which can be attributed to downregulation of activity in Esr1 (estrogen receptor-1)-expressing GABAergic neurons. Enhancing activity of these neurons ameliorates depressive-like behaviors in HW-treated mice, whereas reducing their activity results in expression of these behaviors. Two separate subpopulations mediate different symptoms: a subpopulation projecting to the ventral tegmental area (VTA) mediates anhedonia and another projecting to the periaqueductal gray mediates immobility. These projections enhance activity of dopaminergic neurons in the VTA and serotonergic neurons in the dorsal raphe, respectively, with increased release of dopamine and serotonin, possibly through disinhibition mechanisms. Thus, the MPOA is a hub that mediates depressive-like behaviors resulting from transitions in reproductive hormone levels.
Topics: Mice; Female; Animals; Preoptic Area; Ventral Tegmental Area; Dopaminergic Neurons; GABAergic Neurons
PubMed: 37524978
DOI: 10.1038/s41593-023-01397-2 -
Molecular Biology Reports Jul 2023Parkinson's disease (PD) is a progressive neurodegenerative disease (NDD) caused by dopaminergic neuron degeneration in the substantia nigra (SN). Orexin is a... (Review)
Review
Parkinson's disease (PD) is a progressive neurodegenerative disease (NDD) caused by dopaminergic neuron degeneration in the substantia nigra (SN). Orexin is a neuropeptide that plays a role in the pathogenesis of PD. Orexin has neuroprotective properties in dopaminergic neurons. In PD neuropathology, there is also degeneration of orexinergic neurons in the hypothalamus, in addition to dopaminergic neurons. However, the loss of orexinergic neurons in PD began after the degeneration of dopaminergic neurons. Reduced activity of orexinergic neurons has been linked to developing and progressing motor and non-motor symptoms in PD. In addition, the dysregulation of the orexin pathway is linked to the development of sleep disorders. The hypothalamic orexin pathway regulates various aspects of PD neuropathology at the cellular, subcellular, and molecular levels. Finally, non-motor symptoms, particularly insomnia and disturbed sleep, promote neuroinflammation and the accumulation of neurotoxic proteins as a result of defects in autophagy, endoplasmic reticulum (ER) stress, and the glymphatic system. As a result, this review aimed to highlight the potential role of orexin in PD neuropathology.
Topics: Humans; Orexins; Parkinson Disease; Neurodegenerative Diseases; Neuropeptides; Dopaminergic Neurons
PubMed: 37155018
DOI: 10.1007/s11033-023-08459-5 -
Movement Disorders : Official Journal... Jul 2023The endotoxin hypothesis of Parkinson's disease (PD) is the idea that lipopolysaccharide (LPS) endotoxins contribute to the pathogenesis of this disorder. LPS endotoxins... (Review)
Review
The endotoxin hypothesis of Parkinson's disease (PD) is the idea that lipopolysaccharide (LPS) endotoxins contribute to the pathogenesis of this disorder. LPS endotoxins are found in, and released from, the outer membrane of Gram-negative bacteria, for example in the gut. It is proposed that gut dysfunction in early PD leads to elevated LPS levels in the gut wall and blood, which promotes both α-synuclein aggregation in the enteric neurons and a peripheral inflammatory response. Communication to the brain via circulating LPS and cytokines in the blood and/or the gut-brain axis leads to neuroinflammation and spreading of α-synuclein pathology, exacerbating neurodegeneration in brainstem nuclei and loss of dopaminergic neurons in the substantia nigra, and manifesting in the clinical symptoms of PD. The evidence supporting this hypothesis includes: (1) gut dysfunction, permeability, and bacterial changes occur early in PD, (2) serum levels of LPS are increased in a proportion of PD patients, (3) LPS induces α-synuclein expression, aggregation, and neurotoxicity, (4) LPS causes activation of peripheral monocytes leading to inflammatory cytokine production, and (5) blood LPS causes brain inflammation and specific loss of midbrain dopaminergic neurons, mediated by microglia. If the hypothesis is correct, then treatment options might include: (1) changing the gut microbiome, (2) reducing gut permeability, (3) reducing circulating LPS levels, or (4) blocking the response of immune cells and microglia to LPS. However, the hypothesis has a number of limitations and requires further testing, in particular whether reducing LPS levels can reduce PD incidence, progression, or severity. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Humans; Parkinson Disease; alpha-Synuclein; Endotoxins; Lipopolysaccharides; Dopaminergic Neurons
PubMed: 37157885
DOI: 10.1002/mds.29432 -
Nature Nov 2023Resource-seeking behaviours are ordinarily constrained by physiological needs and threats of danger, and the loss of these controls is associated with pathological...
Resource-seeking behaviours are ordinarily constrained by physiological needs and threats of danger, and the loss of these controls is associated with pathological reward seeking. Although dysfunction of the dopaminergic valuation system of the brain is known to contribute towards unconstrained reward seeking, the underlying reasons for this behaviour are unclear. Here we describe dopaminergic neural mechanisms that produce reward seeking despite adverse consequences in Drosophila melanogaster. Odours paired with optogenetic activation of a defined subset of reward-encoding dopaminergic neurons become cues that starved flies seek while neglecting food and enduring electric shock punishment. Unconstrained seeking of reward is not observed after learning with sugar or synthetic engagement of other dopaminergic neuron populations. Antagonism between reward-encoding and punishment-encoding dopaminergic neurons accounts for the perseverance of reward seeking despite punishment, whereas synthetic engagement of the reward-encoding dopaminergic neurons also impairs the ordinary need-dependent dopaminergic valuation of available food. Connectome analyses reveal that the population of reward-encoding dopaminergic neurons receives highly heterogeneous input, consistent with parallel representation of diverse rewards, and recordings demonstrate state-specific gating and satiety-related signals. We propose that a similar dopaminergic valuation system dysfunction is likely to contribute to maladaptive seeking of rewards by mammals.
Topics: Animals; Dopamine; Dopaminergic Neurons; Drosophila melanogaster; Electroshock; Learning; Odorants; Optogenetics; Punishment; Reward; Starvation; Models, Animal
PubMed: 37880370
DOI: 10.1038/s41586-023-06671-8 -
Neurobiology of Disease Aug 2023Parkinson's disease (PD) is currently the fastest growing disabling neurological disorder worldwide, with motor and non-motor symptoms being its main clinical... (Review)
Review
Parkinson's disease (PD) is currently the fastest growing disabling neurological disorder worldwide, with motor and non-motor symptoms being its main clinical manifestations. The primary pathological features include a reduction in the number of dopaminergic neurons in the substantia nigra and decrease in dopamine levels in the nigrostriatal pathway. Existing treatments only alleviate clinical symptoms and do not stop disease progression; slowing down the loss of dopaminergic neurons and stimulating their regeneration are emerging therapies. Preclinical studies have demonstrated that transplantation of dopamine cells generated from human embryonic or induced pluripotent stem cells can restore the loss of dopamine. However, the application of cell transplantation is limited owing to ethical controversies and the restricted source of cells. Until recently, the reprogramming of astrocytes to replenish lost dopaminergic neurons has provided a promising alternative therapy for PD. In addition, repair of mitochondrial perturbations, clearance of damaged mitochondria in astrocytes, and control of astrocyte inflammation may be extensively neuroprotective and beneficial against chronic neuroinflammation in PD. Therefore, this review primarily focuses on the progress and remaining issues in astrocyte reprogramming using transcription factors (TFs) and miRNAs, as well as exploring possible new targets for treating PD by repairing astrocytic mitochondria and reducing astrocytic inflammation.
Topics: Humans; Astrocytes; Dopamine; Parkinson Disease; Dopaminergic Neurons; Inflammation
PubMed: 37433411
DOI: 10.1016/j.nbd.2023.106224