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Cell Reports Jun 2020Cortical pyramidal cells are generated locally, from pre-programmed progenitors, to form functionally distinct areas. By contrast, striatal projection neurons (SPNs) are...
Cortical pyramidal cells are generated locally, from pre-programmed progenitors, to form functionally distinct areas. By contrast, striatal projection neurons (SPNs) are generated remotely from a common source, undergo migration to form mosaics of striosomes and matrix, and become incorporated into functionally distinct sectors. Striatal circuits might thus have a unique logic of developmental organization, distinct from those of the neocortex. We explore this possibility in mice by mapping one set of SPNs, those in striosomes, with striatonigral projections to the dopamine-containing substantia nigra pars compacta (SNpc). Same-age SPNs exhibit topographic striatonigral projections, according to their resident sector. However, the different birth dates of resident SPNs within a given sector specify the destination of their axons within the SNpc. These findings highlight a logic intercalating birth date-dependent and birth date-independent factors in determining the trajectories of SPN axons and organizing specialized units of striatonigral circuitry that could influence behavioral expression and vulnerabilities to disease.
Topics: Animals; Axons; Basal Ganglia; Corpus Striatum; Dopamine; Mice; Neural Pathways; Neurons; Substantia Nigra
PubMed: 32553154
DOI: 10.1016/j.celrep.2020.107778 -
Folia Morphologica 2023Lead-induced neurotoxicity was marked with locomotor and Parkinsonian-like changes. Oligodendrocytes and synucleinopathy were signed to in the pathophysiology of some...
BACKGROUND
Lead-induced neurotoxicity was marked with locomotor and Parkinsonian-like changes. Oligodendrocytes and synucleinopathy were signed to in the pathophysiology of some neurodegenerative diseases. Vitamin D3's (D3) role in substantia nigra pars compacta (SNpc) disorders is debated between neuroscientists. The aim of the study was to investigate lead-induced SNpc neurotoxic changes and explore the possible neuroprotective role of D3 and the possible involvement of oligodendrocytes and α-synuclein.
MATERIALS AND METHODS
This study included 40 adult Wistar rats assigned into four equal groups: control, lead (Pb) (in drinking water, 1,000 mg/L), Pb + D3 (D3 injection, 1,000 IU/kg IM; 3 days/week), and D3. After 8 weeks, the rats were sacrificed, and their midbrain underwent biochemical and immunoblotting analysis. Midbrain paraffin blocks were stained for histological and immunohistochemical assessment.
RESULTS
Lead (Pb) had increased significantly (p < 0.05) nigral α-synuclein and caspase-11 by immunoblotting analysis. Histologically, it induced neurodegeneration in SNpc and significantly decreased neuronal cell density by cresyl violet staining. Pb also significantly reduced SNpc tyrosine hydroxylase immunoreaction, significantly elevated glial fibrillatory acid protein (GFAP) and α-synuclein immunoreaction associated with a mild but significant increase in caspase-3. In the Pb + D3 group, all the previous deleterious changes were significantly alleviated in addition to significant upregulation of anti-oligodendrocytes immunoexpression.
CONCLUSIONS
Lead (Pb) may induce SNpc neurotoxicity presumably via activation of caspase-11 and α-synuclein. D3 may modulate this neurotoxicity probably through an oligodendrogenic effect.
Topics: Rats; Animals; Pars Compacta; alpha-Synuclein; Synucleinopathies; Lead; Rats, Wistar; Cholecalciferol
PubMed: 35099046
DOI: 10.5603/FM.a2022.0003 -
Frontiers in Neuroscience 2021Parkinson's disease (PD) is a neurodegenerative condition characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) in the midbrain... (Review)
Review
Parkinson's disease (PD) is a neurodegenerative condition characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) in the midbrain resulting in progressive impairment in cognitive and motor abilities. The physiological and molecular mechanisms triggering dopaminergic neuronal loss are not entirely defined. PD occurrence is associated with various genetic and environmental factors causing inflammation and mitochondrial dysfunction in the brain, leading to oxidative stress, proteinopathy, and reduced viability of dopaminergic neurons. Oxidative stress affects the conformation and function of ions, proteins, and lipids, provoking mitochondrial DNA (mtDNA) mutation and dysfunction. The disruption of protein homeostasis induces the aggregation of alpha-synuclein (α-SYN) and parkin and a deficit in proteasome degradation. Also, oxidative stress affects dopamine release by activating ATP-sensitive potassium channels. The cholinergic system is essential in modulating the striatal cells regulating cognitive and motor functions. Several muscarinic acetylcholine receptors (mAChR) and nicotinic acetylcholine receptors (nAChRs) are expressed in the striatum. The nAChRs signaling reduces neuroinflammation and facilitates neuronal survival, neurotransmitter release, and synaptic plasticity. Since there is a deficit in the nAChRs in PD, inhibiting nAChRs loss in the striatum may help prevent dopaminergic neurons loss in the striatum and its pathological consequences. The nAChRs can also stimulate other brain cells supporting cognitive and motor functions. This review discusses the cholinergic system as a therapeutic target of cotinine to prevent cognitive symptoms and transition to dementia in PD.
PubMed: 34616271
DOI: 10.3389/fnins.2021.665820 -
Parkinsonism & Related Disorders Feb 2024The four features of Parkinson's disease (PD), which also manifests other non-motor symptoms, are bradykinesia, tremor, postural instability, and stiffness. The... (Review)
Review
The four features of Parkinson's disease (PD), which also manifests other non-motor symptoms, are bradykinesia, tremor, postural instability, and stiffness. The pathogenic causes of Parkinsonism include Lewy bodies, intracellular protein clumps of αsynuclein, and the degeneration of dopaminergic neurons in the substantia nigra's pars compacta region. The pathophysiology of PD is still poorly understood due to the complexity of the illness. The apoptotic cell death of neurons in PD, however, has been linked to a variety of intracellular mechanisms, according to a wide spectrum of study. The endoplasmic reticulum's stress, decreased levels of neurotrophic factors, oxidative stress, mitochondrial dysfunction, catabolic alterations in dopamine, and decreased activity of tyrosine hydroxylase are some of these causes. The herbicide paraquat has been used in laboratory studies to create a variety of PD pathological features in numerous in-vitro and in-vivo animals. Due to the unique neurotoxicity that paraquat causes, understanding of the pathophysiology of PD has changed. Parkinson's disease (PD) is more likely to develop among people exposed to paraquat over an extended period of time, according to epidemiological studies. Thanks to this paradigm, the hunt for new therapy targets for PD has expanded. In both in-vitro and in-vivo models, the purpose of this study is to summarise the relationship between paraquat exposure and the onset of Parkinson's disease (PD).
Topics: Humans; Animals; Paraquat; Herbicides; Parkinson Disease; Parkinsonian Disorders; Dopaminergic Neurons
PubMed: 38008593
DOI: 10.1016/j.parkreldis.2023.105932 -
Frontiers in Cellular Neuroscience 2022Parkinson's disease (PD), a common neurodegenerative disease characterized by motor dysfunction, results from the death of dopaminergic neurons in the substantia nigra... (Review)
Review
Parkinson's disease (PD), a common neurodegenerative disease characterized by motor dysfunction, results from the death of dopaminergic neurons in the substantia nigra pars compacta (SNc). Although the precise causes of PD are still unknown, several risk factors for PD have been determined, including aging, genetic mutations, environmental factors, and gender. Currently, the molecular mechanisms underlying risk factor-related neurodegeneration in PD remain elusive. Endoplasmic reticulum stress, excessive reactive oxygen species production, and impaired autophagy have been implicated in neuronal death in the SNc in PD. Considering that these pathological processes are tightly associated with intracellular Ca, it is reasonable to hypothesize that dysregulation of Ca handling may mediate risk factors-related PD pathogenesis. We review the recent findings on how risk factors cause Ca dyshomeostasis and how aberrant Ca handling triggers dopaminergic neurodegeneration in the SNc in PD, thus putting forward the possibility that manipulation of specific Ca handling proteins and subcellular Ca homeostasis may lead to new promising strategies for PD treatment.
PubMed: 35496903
DOI: 10.3389/fncel.2022.867385 -
The Journal of Physiology Nov 2023A monosynaptic pathway connects the substantia nigra pars compacta (SNpc) to neurons of the dorsal motor nucleus of the vagus (DMV). This monosynaptic pathway modulates...
A monosynaptic pathway connects the substantia nigra pars compacta (SNpc) to neurons of the dorsal motor nucleus of the vagus (DMV). This monosynaptic pathway modulates the vagal control of gastric motility. It is not known, however, whether this nigro-vagal pathway also modulates the tone and motility of the proximal colon. In rats, microinjection of retrograde tracers in the proximal colon and of anterograde tracers in SNpc showed that bilaterally labelled colonic-projecting neurons in the DMV received inputs from SNpc neurons. Microinjections of the ionotropic glutamate receptor agonist, NMDA, in the SNpc increased proximal colonic motility and tone, as measured via a strain gauge aligned with the colonic circular smooth muscle; the motility increase was inhibited by acute subdiaphragmatic vagotomy. Upon transfection of SNpc with pAAV-hSyn-hM3D(Gq)-mCherry, chemogenetic activation of nigro-vagal nerve terminals by brainstem application of clozapine-N-oxide increased the firing rate of DMV neurons and proximal colon motility; both responses were abolished by brainstem pretreatment with the dopaminergic D1-like antagonist SCH23390. Chemogenetic inhibition of nigro-vagal nerve terminals following SNpc transfection with pAAV-hSyn-hM4D(Gi)-mCherry decreased the firing rate of DMV neurons and inhibited proximal colon motility. These data suggest that a nigro-vagal pathway modulates activity of the proximal colon motility tonically via a discrete dopaminergic synapse in a manner dependent on vagal efferent nerve activity. Impairment of this nigro-vagal pathway may contribute to the severely reduced colonic transit and prominent constipation observed in both patients and animal models of parkinsonism. KEY POINTS: Substantia nigra pars compacta (SNpc) neurons are connected to the dorsal motor nucleus of the vagus (DMV) neurons via a presumed direct pathway. Brainstem neurons in the lateral DMV innervate the proximal colon. Colonic-projecting DMV neurons receive inputs from neurons of the SNpc. The nigro-vagal pathway modulates tone and motility of the proximal colon via D1-like receptors in the DMV. The present study provides the mechanistic basis for explaining how SNpc alterations may lead to a high rate of constipation in patients with Parkinson's Disease.
Topics: Humans; Rats; Animals; Stomach; Rats, Sprague-Dawley; Substantia Nigra; Vagus Nerve; Gastrointestinal Motility; Colon; Constipation
PubMed: 37772988
DOI: 10.1113/JP284238 -
Progress in Brain Research 2020Parkinson's disease (PD) has classically been defined as a movement disorder, in which motor symptoms are explained by the aggregation of alpha-synuclein (α-syn) and... (Review)
Review
Parkinson's disease (PD) has classically been defined as a movement disorder, in which motor symptoms are explained by the aggregation of alpha-synuclein (α-syn) and subsequent death of dopaminergic neurons of the substantia nigra pars compacta (SNpc). More recently, the multisystem effects of the disease have been investigated, with the immune system being implicated in a number of these processes in the brain, the blood, and the gut. In this review, we highlight the dysfunctional immune system found in both human PD and animal models of the disease, and discuss how genetic risk factors and risk modifiers are associated with pro-inflammatory immune responses. Finally, we emphasize evidence that the immune response drives the pathogenesis and progression of PD, and discuss key questions that remain to be investigated in order to identify immunomodulatory therapies in PD.
Topics: Adaptive Immunity; Animals; Humans; Immunity, Innate; Inflammation; Parkinson Disease
PubMed: 32247364
DOI: 10.1016/bs.pbr.2019.10.006 -
Current Environmental Health Reports Sep 2021Parkinson's disease (PD) is the most prevalent motor disorder and is characterized by loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) region of... (Review)
Review
PURPOSE OF REVIEW
Parkinson's disease (PD) is the most prevalent motor disorder and is characterized by loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) region of the brain. Though the pathology of PD is well established, the cause of this neuronal loss is not well understood. Approximately 90% of PD cases are sporadic, and the environment plays a significant role in disease pathogenesis. The etiology of PD is highly complex, with neuroinflammation being one of the most critical factors implicated in PD. However, the signaling mechanisms underlying neuroinflammation and its interaction with environmental factors are unclear.
RECENT FINDINGS
Astroglia and microglia are the two principal cells that play an essential role in maintaining neuronal health in many ways, including through immunological means. Exposure to environmental stressors from various sources affects these glial cells leading to chronic and sustained inflammation. Recent epidemiological studies have identified an interaction among environmental factors and glial genes in Parkinson's disease. Mechanistic studies have shown that exposure to pesticides like rotenone and paraquat, neurotoxic metals like manganese and lead, and even diesel exhaust fumes induce glial activation by regulating various key inflammatory pathways, including the inflammasomes, NOX pathways, and others. This review aims to discuss the recent advances in understanding the mechanism of glial induction in response to environmental stressors and discuss the potential role of gene-environment interaction in driving glial activation.
Topics: Dopaminergic Neurons; Gene-Environment Interaction; Humans; Inflammasomes; Microglia; Parkinson Disease
PubMed: 34043217
DOI: 10.1007/s40572-021-00320-w -
ACS Chemical Neuroscience Aug 2022Parkinson's disease (PD) is a neurodegenerative disorder that gradually develops over time in a progressive manner. The main culprit behind the disease pathology is... (Review)
Review
Parkinson's disease (PD) is a neurodegenerative disorder that gradually develops over time in a progressive manner. The main culprit behind the disease pathology is dopaminergic deficiency in Substantia nigra Pars Compacta (SNpc) due to neuronal degeneration. However, there are other factors that are not only associated with it but also somehow responsible for inception of pathology. Metabolic syndrome is one such risk factor for PD. Metabolic syndrome is a cluster of diseases mainly including diabetes, hypertension, obesity, and hyperlipidemia which pose a risk for developing cardiovascular disorders. All of these disorders have their own pathological pathways that intertwine with PD pathology. This leads to alpha-synuclein aggregation, neuroinflammation, mitochondrial dysfunction, and oxidative stress which are facets in initiating PD pathology. Although few reports are available, this area is underexplored and has contradictory views. Hence, further studies are needed in order to establish a definite relationship between PD and metabolic syndrome. In this review, we aim to elucidate the molecular mechanisms to confirm the association between them and pave the way for potential repurposing of therapies.
Topics: Dopaminergic Neurons; Humans; Metabolic Syndrome; Oxidative Stress; Parkinson Disease; Pars Compacta; alpha-Synuclein
PubMed: 35856649
DOI: 10.1021/acschemneuro.2c00165 -
Biomolecules Nov 2022Parkinson's disease (PD) is an incurable neurodegenerative disease of high prevalence, characterized by the prominent death of dopaminergic neurons in the substantia... (Review)
Review
Parkinson's disease (PD) is an incurable neurodegenerative disease of high prevalence, characterized by the prominent death of dopaminergic neurons in the substantia nigra pars compacta, which produces dopamine deficiency, leading to classic motor symptoms. Although PD has traditionally been considered as a neuronal cell autonomous pathology, in which the damage of vulnerable neurons is responsible for the disease, growing evidence strongly suggests that astrocytes might have an active role in the neurodegeneration observed. In the present review, we discuss several studies evidencing astrocyte implications in PD, highlighting the consequences of both the loss of normal homeostatic functions and the gain in toxic functions for the wellbeing of dopaminergic neurons. The revised information provides significant evidence that allows astrocytes to be positioned as crucial players in PD etiology, a factor that needs to be taken into account when considering therapeutic targets for the treatment of the disease.
Topics: Humans; Parkinson Disease; Astrocytes; Substantia Nigra; Neurodegenerative Diseases; Dopaminergic Neurons
PubMed: 36551173
DOI: 10.3390/biom12121745