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Frontiers in Human Neuroscience 2016As Parkinson's disease progresses, a massive loss of dopaminergic neurons is accompanied by accumulation of alpha-Synuclein (αSyn) neuronal inclusions called Lewy... (Review)
Review
As Parkinson's disease progresses, a massive loss of dopaminergic neurons is accompanied by accumulation of alpha-Synuclein (αSyn) neuronal inclusions called Lewy bodies and Lewy neurites. Inclusions first appear in olfactory bulb and enteric neurons then in ascendant neuroanatomical interconnected areas, and finally, in late stages of the disease, Lewy bodies are observed in a substantia nigra pars compacta with clear signs of neuronal loss. It is believed that the spreading of Lewy bodies through the nervous system is a consequence of the cell-to-cell propagation of αSyn, that can occur via sequential steps of secretion and uptake. Certain pathological forms of transmitted αSyn are able to seed endogenous counterparts in healthy recipient cells, thus promoting the self-sustained cycle of inclusion formation, amplification and spreading, that ultimately underlies disease progression. Here we review the cell-to-cell propagation of αSyn focusing on its role in the progression of Parkinson's disease.
PubMed: 27994545
DOI: 10.3389/fnhum.2016.00608 -
Frontiers in Neurology 2019Parkinson's disease is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons of the substantia nigra pars compacta with a reduction of... (Review)
Review
Parkinson's disease is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons of the substantia nigra pars compacta with a reduction of dopamine concentration in the striatum. The complex interaction between genetic and environmental factors seems to play a role in determining susceptibility to PD and may explain the heterogeneity observed in clinical presentations. The exact etiology is not yet clear, but different possible causes have been identified. Inflammation has been increasingly studied as part of the pathophysiology of neurodegenerative diseases, corroborating the hypothesis that the immune system may be the nexus between environmental and genetic factors, and the abnormal immune function can lead to disease. In this review we report the different aspects of inflammation and immune system in Parkinson's disease, with particular interest in the possible role played by immune dysfunctions in PD, with focus on autoimmunity and processes involving infectious agents as a trigger and alpha-synuclein protein (α-syn).
PubMed: 30837941
DOI: 10.3389/fneur.2019.00122 -
Frontiers in Neuroanatomy 2015Parkinson disease (PD) is a chronic, progressive neurological disease that is associated with a loss of dopaminergic neurons in the substantia nigra pars compacta of the... (Review)
Review
Parkinson disease (PD) is a chronic, progressive neurological disease that is associated with a loss of dopaminergic neurons in the substantia nigra pars compacta of the brain. The molecular mechanisms underlying the loss of these neurons still remain elusive. Oxidative stress is thought to play an important role in dopaminergic neurotoxicity. Complex I deficiencies of the respiratory chain account for the majority of unfavorable neuronal degeneration in PD. Environmental factors, such as neurotoxins, pesticides, insecticides, dopamine (DA) itself, and genetic mutations in PD-associated proteins contribute to mitochondrial dysfunction which precedes reactive oxygen species formation. In this mini review, we give an update of the classical pathways involving these mechanisms of neurodegeneration, the biochemical and molecular events that mediate or regulate DA neuronal vulnerability, and the role of PD-related gene products in modulating cellular responses to oxidative stress in the course of the neurodegenerative process.
PubMed: 26217195
DOI: 10.3389/fnana.2015.00091 -
Frontiers in Neuroscience 2015Parkinson's disease is one of the most common neurodegenerative diseases. Animal models have contributed a large part to our understanding and therapeutics developed for... (Review)
Review
Parkinson's disease is one of the most common neurodegenerative diseases. Animal models have contributed a large part to our understanding and therapeutics developed for treatment of PD. There are several more exhaustive reviews of literature that provide the initiated insights into the specific models; however a novel synthesis of the basic advantages and disadvantages of different models is much needed. Here we compare both neurotoxin based and genetic models while suggesting some novel avenues in PD modeling. We also highlight the problems faced and promises of all the mammalian models with the hope of providing a framework for comparison of various systems.
PubMed: 26834536
DOI: 10.3389/fnins.2015.00503 -
Journal of Research in Medical Sciences... 2016At present, when a clinical diagnosis of Parkinson's disease (PD) is made, serious damage has already been done to nerve cells of the substantia nigra pars compacta. The... (Review)
Review
At present, when a clinical diagnosis of Parkinson's disease (PD) is made, serious damage has already been done to nerve cells of the substantia nigra pars compacta. The diagnosis of PD in its earlier stages, before this irreversible damage, would be of enormous benefit for future treatment strategies designed to slow or halt the progression of this disease that possibly prevents accumulation of toxic aggregates. As a molecular biomarker for the detection of PD in its earlier stages, alpha-synuclein (α-syn), which is a key component of Lewy bodies, in which it is found in an aggregated and fibrillar form, has attracted considerable attention. Here, α-syn is reviewed in details.
PubMed: 27904575
DOI: 10.4103/1735-1995.181989 -
Brain : a Journal of Neurology Dec 2021Misfolding and aggregation of α-synuclein are specific features of Parkinson's disease and other neurodegenerative diseases defined as synucleinopathies. Parkinson's...
Misfolding and aggregation of α-synuclein are specific features of Parkinson's disease and other neurodegenerative diseases defined as synucleinopathies. Parkinson's disease progression has been correlated with the formation and extracellular release of α-synuclein aggregates, as well as with their spread from neuron to neuron. Therapeutic interventions in the initial stages of Parkinson's disease require a clear understanding of the mechanisms by which α-synuclein disrupts the physiological synaptic and plastic activity of the basal ganglia. For this reason, we identified two early time points to clarify how the intrastriatal injection of α-synuclein-preformed fibrils in rodents via retrograde transmission induces time-dependent electrophysiological and behavioural alterations. We found that intrastriatal α-synuclein-preformed fibrils perturb the firing rate of dopaminergic neurons in the substantia nigra pars compacta, while the discharge of putative GABAergic cells of the substantia nigra pars reticulata is unchanged. The α-synuclein-induced dysregulation of nigrostriatal function also impairs, in a time-dependent manner, the two main forms of striatal synaptic plasticity, long-term potentiation and long-term depression. We also observed an increased glutamatergic transmission measured as an augmented frequency of spontaneous excitatory synaptic currents. These changes in neuronal function in the substantia nigra pars compacta and striatum were observed before overt neuronal death occurred. In an additional set of experiments, we were able to rescue α-synuclein-induced alterations of motor function, striatal synaptic plasticity and increased spontaneous excitatory synaptic currents by subchronic treatment with l-DOPA, a precursor of dopamine widely used in the therapy of Parkinson's disease, clearly demonstrating that a dysfunctional dopamine system plays a critical role in the early phases of the disease.
Topics: Animals; Dopamine; Dopaminergic Neurons; Male; Neuronal Plasticity; Parkinson Disease; Rats; Rats, Wistar; Substantia Nigra; Synaptic Transmission; alpha-Synuclein
PubMed: 34297092
DOI: 10.1093/brain/awab242 -
Journal of Enzyme Inhibition and... Dec 2023Parkinson's disease (PD) is characterised by progressive death of dopamine (DA) neurons in the substantia nigra pars compacta (SNpc) and pathological accumulation of... (Review)
Review
Parkinson's disease (PD) is characterised by progressive death of dopamine (DA) neurons in the substantia nigra pars compacta (SNpc) and pathological accumulation of α-synuclein fibrils, as well as central nervous system inflammation. Elevated levels of central inflammatory factors in PD disrupt the kynurenine pathway (KP) and favour the activation of excitotoxic branches, leading to a significant reduction in the neuroprotective metabolite kynurenic acid (KYNA) and a significant increase in the neurotoxic metabolite quinolinic acid (QUIN), which exacerbates excitotoxicity and amplifies the inflammatory response, closely related to the occurrence and development of PD. KYNA analogs, precursor drugs, and KP enzyme modulators may represent a new therapeutic strategy for PD. This article reviews the role of KP in the neurodegenerative pathology of PD and its prevention and treatment, aiming to provide necessary theoretical basis and new ideas for the study of the neurobiological mechanisms underlying PD-related behavioural dysfunction and targeted interventions.
Topics: Humans; Parkinson Disease; Kynurenine; Central Nervous System; Inflammation
PubMed: 37381707
DOI: 10.1080/14756366.2023.2225800 -
Frontiers in Aging Neuroscience 2018The pedunculopontine nucleus (PPN) is situated in the upper pons in the dorsolateral portion of the ponto-mesencephalic tegmentum. Its main mass is positioned at the... (Review)
Review
The pedunculopontine nucleus (PPN) is situated in the upper pons in the dorsolateral portion of the ponto-mesencephalic tegmentum. Its main mass is positioned at the trochlear nucleus level, and is part of the mesenphalic locomotor region (MLR) in the upper brainstem. The human PPN is divided into two subnuclei, the pars compacta (PPNc) and pars dissipatus (PPNd), and constitutes both cholinergic and non-cholinergic neurons with afferent and efferent projections to the cerebral cortex, thalamus, basal ganglia (BG), cerebellum, and spinal cord. The BG controls locomotion and posture via GABAergic output of the substantia nigra pars reticulate (SNr). In PD patients, GABAergic BG output levels are abnormally increased, and gait disturbances are produced via abnormal increases in SNr-induced inhibition of the MLR. Since the PPN is vastly connected with the BG and the brainstem, dysfunction within these systems lead to advanced symptomatic progression in Parkinson's disease (PD), including sleep and cognitive issues. To date, the best treatment is to perform deep brain stimulation (DBS) on PD patients as outcomes have shown positive effects in ameliorating the debilitating symptoms of this disease by treating pathological circuitries within the parkinsonian brain. It is therefore important to address the challenges and develop this procedure to improve the quality of life of PD patients.
PubMed: 29755338
DOI: 10.3389/fnagi.2018.00099 -
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 -
Movement Disorders : Official Journal... Mar 2023Susceptibility magnetic resonance imaging (MRI) is sensitive to iron-related changes in the substantia nigra pars compacta (SNc), the key pathologic locus of...
BACKGROUND
Susceptibility magnetic resonance imaging (MRI) is sensitive to iron-related changes in the substantia nigra pars compacta (SNc), the key pathologic locus of parkinsonisms. It is unclear, however, if iron deposition in the SNc is associated with its neurodegeneration.
OBJECTIVE
The objective of this study was to test whether susceptibility MRI metrics in parkinsonisms are associated with SNc neuropathologic features of dopaminergic neuron loss, gliosis, and α-synuclein and tau burden.
METHODS
This retrospective study included 27 subjects with both in vivo MRI and postmortem data. Multigradient echo imaging was used to derive the apparent transverse relaxation rate (R2*) and quantitative susceptibility mapping (QSM) in the SNc. Archived midbrain slides that were stained with hematoxylin and eosin, anti-α-synuclein, and anti-tau were digitized to quantify neuromelanin-positive neuron density, glial density, and the percentages of area occupied by positive α-synuclein and tau staining. MRI-histology associations were examined using Pearson correlations and regression.
RESULTS
Twenty-four subjects had postmortem parkinsonism diagnoses (Lewy body disorder, progressive supranuclear palsy, multiple system atrophy, and corticobasal degeneration), two had only Alzheimer's neuropathology, and one exhibited only mild atrophy. Among all subjects, both R2* and QSM were associated with glial density (r ≥ 0.67; P < 0.001) and log-transformed tau burden (r ≥ 0.53; P ≤ 0.007). Multiple linear regression identified glial density and log-transformed tau as determinants for both MRI metrics (R ≥ 0.580; P < 0.0001). Neither MRI metric was associated with neuron density or α-synuclein burden.
CONCLUSIONS
R2* and QSM are associated with both glial density and tau burden, key neuropathologic features in the parkinsonism SNc. © 2023 International Parkinson and Movement Disorder Society.
Topics: Humans; Pars Compacta; Parkinson Disease; Substantia Nigra; Retrospective Studies; Parkinsonian Disorders; Magnetic Resonance Imaging; Iron
PubMed: 36598274
DOI: 10.1002/mds.29311