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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 -
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 -
Current Drug Research Reviews 2021Evidence has emerged over the last 2 decades to ascertain the proof of concepts viz. mitochondrial dysfunction, inflammation-derived oxidative damage and... (Review)
Review
Evidence has emerged over the last 2 decades to ascertain the proof of concepts viz. mitochondrial dysfunction, inflammation-derived oxidative damage and cytokine-induced toxicity that play a significant role in Parkinson's disease (PD). The available pharmacotherapies for PD are mainly symptomatic and typically indicate L-DOPA to restrain dopamine deficiency and its consequences. In the 21st century, the role of antibiotics has emerged at the forefront of medicines in health and human illness. There are several experimental and pre-clinical evidences that support the potential use of antibiotics as a neuroprotective agent. The astonishing effects of antibiotics and their neuroprotective properties against neurodegeneration and neuro-inflammation would be phenomenal for the development of effective therapy against PD. Antibiotics are also testified as useful in not only preventing the formation of alpha-synuclein but also acting on mitochondrial dysfunction and neuro-inflammation. Thus, the possible therapy with antibiotics in PD would impact both pathways leading to neuronal cell death in substantia nigra and pars compacta in the midbrain. Moreover, the antibiotic-based pharmacotherapy will open a scientific research avenue to add more to the evidence-based and rational use of antibiotics for the treatment and management of PD and other neurodegenerative disorders.
Topics: Anti-Bacterial Agents; Humans; Levodopa; Parkinson Disease; Pars Compacta; Substantia Nigra
PubMed: 33719951
DOI: 10.2174/2589977513666210315095133 -
Frontiers in Neuroscience 2021Parkinson's disease (PD) is a severely debilitating neurodegenerative disease, affecting the motor system, leading to resting tremor, cogwheel rigidity, bradykinesia,... (Review)
Review
Parkinson's disease (PD) is a severely debilitating neurodegenerative disease, affecting the motor system, leading to resting tremor, cogwheel rigidity, bradykinesia, walking and gait difficulties, and postural instability. The severe loss of dopaminergic neurons in the substantia nigra pars compacta causes striatal dopamine deficiency and the presence of Lewy bodies indicates a pathological hallmark of PD. Although the current treatment of PD aims to preserve dopaminergic neurons or to replace dopamine depletion in the brain, it is notable that complete recovery from the disease is yet to be achieved. Given the complexity and multisystem effects of PD, the underlying mechanisms of PD pathogenesis are yet to be elucidated. The advancement of medical technologies has given some insights in understanding the mechanism and potential treatment of PD with a special interest in the role of microRNAs (miRNAs) to unravel the pathophysiology of PD. In PD patients, it was found that striatal brain tissue and dopaminergic neurons from the substantia nigra demonstrated dysregulated miRNAs expression profiles. Hence, dysregulation of miRNAs may contribute to the pathogenesis of PD through modulation of PD-associated gene and protein expression. This review will discuss recent findings on PD-associated miRNAs dysregulation, from the regulation of PD-associated genes, dopaminergic neuron survival, α-synuclein-induced inflammation and circulating miRNAs. The next section of this review also provides an update on the potential uses of miRNAs as diagnostic biomarkers and therapeutic tools for PD.
PubMed: 33994934
DOI: 10.3389/fnins.2021.660379 -
Cell Calcium Jul 2020Parkinson's disease (PD) is a major health problem worldwide affecting millions of people and is a result of neurodegeneration in a small part of the brain known as... (Review)
Review
Parkinson's disease (PD) is a major health problem worldwide affecting millions of people and is a result of neurodegeneration in a small part of the brain known as substantia nigra pars compacta. Aberration in mitochondrial Ca homeostasis plays, among several other factors, an important role for the neuronal loss in PD. Mitochondria are vital for cellular physiology, e.g. for ATP generation, and mitochondrial Ca is a key player in cell functioning and survival. Mitochondrial Ca homeostasis is maintained by a fine balance between the activities of proteins mediating the influx and efflux of Ca across mitochondrial membranes. Malfunctioning of these proteins leading to Ca overload promotes ROS generation, which induces cell death by triggering the opening of mitochondrial permeability transition pore. Till now PD remains incurable and the "gold standard" drug which can only delays the disease progression is l-Dopa from the 1960s and therefore, the situation warrants the search for novel targets for the treatment of the PD patients. In this review, we summarize the current views that suggest mitochondrial Ca regulatory pathways are good candidates for the treatment of PD.
Topics: Animals; Calcium; Calcium Signaling; Humans; Mitochondria; Models, Biological; Molecular Targeted Therapy; Parkinson Disease
PubMed: 32473487
DOI: 10.1016/j.ceca.2020.102216 -
Nature Neuroscience Mar 2024Evidence of direct reciprocal connections between the cerebellum and basal ganglia has challenged the long-held notion that these structures function independently....
Evidence of direct reciprocal connections between the cerebellum and basal ganglia has challenged the long-held notion that these structures function independently. While anatomical studies have suggested the presence of cerebellar projections to the substantia nigra pars compacta (SNc), the nature and function of these connections (Cb-SNc) is unknown. Here we show, in mice, that Cb-SNc projections form monosynaptic glutamatergic synapses with dopaminergic and non-dopaminergic neurons in the SNc. Optogenetic activation of Cb-SNc axons in the SNc is associated with increased SNc activity, elevated striatal dopamine levels and increased locomotion. During behavior, Cb-SNc projections are bilaterally activated before ambulation and unilateral lever manipulation. Cb-SNc projections show prominent activation for water reward and higher activation for sweet water, suggesting that the pathway also encodes reward value. Thus, the cerebellum directly, rapidly and effectively modulates basal ganglia dopamine levels and conveys information related to movement initiation, vigor and reward processing.
Topics: Mice; Animals; Dopamine; Substantia Nigra; Locomotion; Cerebellum; Water
PubMed: 38272967
DOI: 10.1038/s41593-023-01560-9 -
Current Drug Targets 2022Parkinson's disease is a chronic and gradually progressive neurodegenerative disorder triggered due to the loss of dopamine-releasing neurons in the region of substantia... (Review)
Review
Parkinson's disease is a chronic and gradually progressive neurodegenerative disorder triggered due to the loss of dopamine-releasing neurons in the region of substantia nigra pars compacta characterized by the motor symptoms, such as tremor, bradykinesia, akinesia, and postural instability. Proteinopathies, mitochondrial dysfunction induced dopaminergic neuronal deterioration, and gene mutations are the hallmarks of Parkinson's disease. The bioactive components of Brahmi, such as Bacoside A, Bacoside B, and Bacosaponins, belong to various chemical families. Brahmi's neuroprotective role includes reducing neuronal oxidative stress, dopaminergic neuronal degeneration, mitochondrial dysfunction, inflammation, inhibition of α-synuclein aggregation, and improvement of cognitive and learning behaviour. Researchers found that Bacopa monnieri significantly increased brain levels of glutathione, vitamin C, vitamin E, and vitamin A in rats exposed to cigarette smoke. Brahmi has a potent antioxidant property and neuroprotective effects against PD that help reduce oxidative stress and neuroinflammation and enhance dopamine levels. The review collates all the preclinical studies that prove the beneficial neuroprotective effect of Brahmi for treating PD.
Topics: Animals; Bacopa; Dopamine; Dopaminergic Neurons; Neuroprotective Agents; Oxidative Stress; Parkinson Disease; Rats
PubMed: 35297345
DOI: 10.2174/1389450123666220316091734 -
Cells Jan 2020Parkinson's disease (PD) is one of the main neurodegenerative disease characterized by a progressive degeneration of neurons constituted by dopamine in the substantia... (Review)
Review
Parkinson's disease (PD) is one of the main neurodegenerative disease characterized by a progressive degeneration of neurons constituted by dopamine in the substantia nigra pars compacta. The etiologies of PD remain unclear. Aging is the main risk factor for PD. Aging could dysregulate molecular pathways controlling cell homeostatic mechanisms. PD cells are the sites of several metabolic abnormalities including neuroinflammation and oxidative stress. Metabolic structures are driven by circadian rhythms. Biologic rhythms are complex systems interacting with the environment and controlling several physiological pathways. Recent findings have shown that the dysregulation of the circadian rhythms is correlated with PD and its metabolic dysregulations. This review is focused on the key role of circadian rhythms and their impact on neuroinflammation and oxidative stress in Parkinson's disease.
Topics: Brain; Circadian Rhythm; Humans; Inflammation; Melatonin; Oxidative Stress; Parkinson Disease
PubMed: 32012898
DOI: 10.3390/cells9020314 -
Neurochemistry International Jan 2023Parkinson's disease is the second most common neurodegenerative disease which is characterized by selective degeneration of dopaminergic neurons in the substantia nigra... (Review)
Review
Parkinson's disease is the second most common neurodegenerative disease which is characterized by selective degeneration of dopaminergic neurons in the substantia nigra pars compacta. The intrinsic neuronal firing activity is critical for the functional organization of brain and the specific deficits of neuronal firing activity may be associated with different brain disorders. It is known that the surviving nigra dopaminergic neurons exhibit altered firing activity, such as decreased spontaneous firing frequency, reduced number of firing neurons and increased burst firing in Parkinson's disease. Several ionic mechanisms are involved in changed firing activity of dopaminergic neurons under parkinsonian state. In this review, we summarize the changes of spontaneous firing activity as well as the possible mechanisms of nigra dopaminergic neurons in Parkinson's disease. This review may let us clearly understand the involvement of neuronal firing activity of nigra dopaminergic neurons in Parkinson's disease.
Topics: Humans; Parkinson Disease; Dopaminergic Neurons; Neurodegenerative Diseases; Substantia Nigra
PubMed: 36563966
DOI: 10.1016/j.neuint.2022.105465 -
Frontiers in Aging Neuroscience 2022Parkinson's disease (PD) is one of the most common neurodegenerative movement disorders worldwide. There are currently no cures or preventative treatments for PD.... (Review)
Review
Parkinson's disease (PD) is one of the most common neurodegenerative movement disorders worldwide. There are currently no cures or preventative treatments for PD. Emerging evidence indicates that mitochondrial dysfunction is closely associated with pathogenesis of sporadic and familial PD. Because dopaminergic neurons have high energy demand, cells affected by PD exhibit mitochondrial dysfunction that promotes the disease-defining the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The mitochondrion has a particularly important role as the cellular "powerhouse" of dopaminergic neurons. Therefore, mitochondria have become a promising therapeutic target for PD treatments. This review aims to describe mitochondrial dysfunction in the pathology of PD, outline the genes associated with familial PD and the factors related to sporadic PD, summarize current knowledge on mitochondrial quality control in PD, and give an overview of therapeutic strategies for targeting mitochondria in neuroprotective interventions in PD.
PubMed: 35795234
DOI: 10.3389/fnagi.2022.885500