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International Journal of Molecular... May 2023Disease modeling in non-human subjects is an essential part of any clinical research. To gain proper understanding of the etiology and pathophysiology of any disease,... (Review)
Review
Disease modeling in non-human subjects is an essential part of any clinical research. To gain proper understanding of the etiology and pathophysiology of any disease, experimental models are required to replicate the disease process. Due to the huge diversity in pathophysiology and prognosis in different diseases, animal modeling is customized and specific accordingly. As in other neurodegenerative diseases, Parkinson's disease is a progressive disorder coupled with varying forms of physical and mental disabilities. The pathological hallmarks of Parkinson's disease are associated with the accumulation of misfolded protein called α-synuclein as Lewy body, and degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) area affecting the patient's motor activity. Extensive research has already been conducted regarding animal modeling of Parkinson's diseases. These include animal systems with induction of Parkinson's, either pharmacologically or via genetic manipulation. In this review, we will be summarizing and discussing some of the commonly employed Parkinson's disease animal model systems and their applications and limitations.
Topics: Animals; Parkinson Disease; alpha-Synuclein; Pars Compacta; Lewy Bodies; Disease Models, Animal; Dopaminergic Neurons; Substantia Nigra
PubMed: 37240432
DOI: 10.3390/ijms24109088 -
Progress in Brain Research 2020Parkinson's disease (PD) is the second most common neurodegenerative disease, disabling millions worldwide. Despite the imperative PD poses, at present, there is no cure... (Review)
Review
Parkinson's disease (PD) is the second most common neurodegenerative disease, disabling millions worldwide. Despite the imperative PD poses, at present, there is no cure or means of slowing progression. This gap is attributable to our incomplete understanding of the factors driving pathogenesis. Research over the past several decades suggests that both cell-autonomous and non-cell autonomous processes contribute to the neuronal dysfunction underlying PD symptoms. The thesis of this review is that an intersection of these processes governs the pattern of pathology in PD. Studies of substantia nigra pars compacta (SNc) dopaminergic neurons, whose loss is responsible for the core motor symptoms of PD, suggest that they have a combination of traits-a long, highly branched axon, autonomous activity, and elevated mitochondrial oxidant stress-that predispose them to non-cell autonomous drivers of pathogenesis, like misfolded forms of alpha-synuclein (α-SYN) and inflammation. The literature surrounding these issues will be briefly summarized, and the translational implications of an intersectional hypothesis of PD pathogenesis discussed.
Topics: Dopaminergic Neurons; Humans; Mitochondria; Parkinson Disease; alpha-Synuclein
PubMed: 32247375
DOI: 10.1016/bs.pbr.2020.02.005 -
Cellular and Molecular Neurobiology Nov 2023Parkinson's disease (PD) is caused due to degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) which leads to the depletion of dopamine in... (Review)
Review
Parkinson's disease (PD) is caused due to degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) which leads to the depletion of dopamine in the body. The lack of dopamine is mainly due to aggregation of misfolded α-synuclein which causes motor impairment in PD. Dopamine is also required for normal retinal function and the light-dark vision cycle. Misfolded α-synuclein present in inner retinal layers causes vision-associated problems in PD patients. Hence, individuals with PD also experience structural and functional changes in the retina. Mutation in LRRK2, PARK2, PARK7, PINK1, or SNCA genes and mitochondria dysfunction also play a role in the pathophysiology of PD. In this review, we discussed the different etiologies which lead to PD and future prospects of employing non-invasive techniques and retinal changes to diagnose the onset of PD earlier.
Topics: Humans; Parkinson Disease; alpha-Synuclein; Dopamine; Substantia Nigra; Dopaminergic Neurons; Early Diagnosis; Retina
PubMed: 37831228
DOI: 10.1007/s10571-023-01419-4 -
Neurochemical Research Oct 2023Parkinson's disease is a neurodegenerative disease affecting mainly the elderly population. It is characterized by the loss of dopaminergic neurons of the substantia... (Review)
Review
Parkinson's disease is a neurodegenerative disease affecting mainly the elderly population. It is characterized by the loss of dopaminergic neurons of the substantia nigra pars compacta region. Parkinson's disease patients exhibit motor symptoms like tremors, rigidity, bradykinesia/hypokinesia, and non-motor symptoms like depression, cognitive decline, delusion, and pain. Major pathophysiological factors which contribute to neuron loss include excess/misfolded alpha-synuclein aggregates, microglial cell-mediated neuroinflammation, excitotoxicity, oxidative stress, and defective mitochondrial function. Sigma-1 receptors are molecular chaperones located at mitochondria-associated ER membrane. Their activation (by endogenous ligands or agonists) has shown neuroprotective and neurorestorative effects in various diseases. This review discusses the roles of activated Sig-1 receptors in modulating various pathophysiological features of Parkinson's disease like alpha-synuclein aggregates, neuroinflammation, excitotoxicity, and oxidative stress.
Topics: Aged; Humans; Parkinson Disease; alpha-Synuclein; Neurodegenerative Diseases; Neuroinflammatory Diseases; Dopaminergic Neurons; Substantia Nigra; Sigma-1 Receptor
PubMed: 37259012
DOI: 10.1007/s11064-023-03960-6 -
Frontiers in Pharmacology 2020Nowadays it is well accepted that in Parkinson's disease (PD), the neurodegenerative process occurs in stages and that damage to other areas precedes the neuronal loss... (Review)
Review
Nowadays it is well accepted that in Parkinson's disease (PD), the neurodegenerative process occurs in stages and that damage to other areas precedes the neuronal loss in the substantia nigra pars compacta, which is considered a pathophysiological hallmark of PD. This heterogeneous and progressive neurodegeneration may explain the diverse symptomatology of the disease, including motor and non-motor alterations. In PD, one of the first areas undergoing degeneration is the locus coeruleus (LC). This noradrenergic nucleus provides extensive innervation throughout the brain and plays a fundamental neuromodulator role, participating in stress responses, emotional memory, and control of motor, sensory, and autonomic functions. Early in the disease, LC neurons suffer modifications that can condition the effectiveness of pharmacological treatments, and importantly, can lead to the appearance of common non-motor symptomatology. The noradrenergic system also exerts anti-inflammatory and neuroprotective effect on the dopaminergic degeneration and noradrenergic damage can consequently condition the progress of the disease. From the pharmacological point of view, it is also important to understand how the noradrenergic system performs in PD, since noradrenergic medication is often used in these patients, and drug interactions can take place when combining them with the gold standard drug therapy in PD, L-3,4-dihydroxyphenylalanine (L-DOPA). This review provides an overview about the functional status of the noradrenergic system in PD and its contribution to the efficacy of pharmacological-based treatments. Based on preclinical and clinical publications, a special attention will be dedicated to the most prevalent non-motor symptoms of the disease.
PubMed: 32322208
DOI: 10.3389/fphar.2020.00435 -
Journal of Neural Transmission (Vienna,... May 2020Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. Behind the symptoms there is a complex pathological mechanism which leads to a... (Review)
Review
Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. Behind the symptoms there is a complex pathological mechanism which leads to a dopaminergic cell loss in the substantia nigra pars compacta. Despite the strong efforts, curative treatment has not been found yet. To prevent a further cell death, numerous molecules were tested in terms of neuroprotection in preclinical (in vitro, in vivo) and in clinical studies as well. The aim of this review article is to summarize our knowledge about the extensively tested neuroprotective agents (Search period: 1991-2019). We detail the underlying pathological mechanism and summarize the most important results of the completed animal and clinical trials. Although many positive results have been reported in the literature, there is still no evidence that any of them should be used in clinical practice (Cochrane analysis was performed). Therefore, further studies are needed to better understand the pathomechanism of PD and to find the optimal neuroprotective agent(s).
Topics: Animals; Humans; Neuroprotective Agents; Parkinson Disease
PubMed: 31828513
DOI: 10.1007/s00702-019-02115-8 -
Movement Disorders : Official Journal... Aug 2019Studies of the pathophysiology of parkinsonism (specifically akinesia and bradykinesia) have a long history and primarily model the consequences of dopamine loss in the... (Review)
Review
Studies of the pathophysiology of parkinsonism (specifically akinesia and bradykinesia) have a long history and primarily model the consequences of dopamine loss in the basal ganglia on the function of the basal ganglia/thalamocortical circuit(s). Changes of firing rates of individual nodes within these circuits were originally considered central to parkinsonism. However, this view has now given way to the belief that changes in firing patterns within the basal ganglia and related nuclei are more important, including the emergence of burst discharges, greater synchrony of firing between neighboring neurons, oscillatory activity patterns, and the excessive coupling of oscillatory activities at different frequencies. Primarily focusing on studies obtained in nonhuman primates and human patients with Parkinson's disease, this review summarizes the current state of this field and highlights several emerging areas of research, including studies of the impact of the heterogeneity of external pallidal neurons on parkinsonism, the importance of extrastriatal dopamine loss, parkinsonism-associated synaptic and morphologic plasticity, and the potential role(s) of the cerebellum and brainstem in the motor dysfunction of Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society.
Topics: Animals; Basal Ganglia; Brain Stem; Brain Waves; Cerebellum; Cerebral Cortex; Dopamine; Electroencephalography; Globus Pallidus; Haplorhini; Humans; Neostriatum; Neural Pathways; Neuronal Plasticity; Parkinson Disease; Parkinsonian Disorders; Pars Compacta; Thalamus
PubMed: 31216379
DOI: 10.1002/mds.27741 -
Biomolecules Jul 2023Manganese (Mn) exposure has evolved from acute, high-level exposure causing manganism to low, chronic lifetime exposure. In this latter scenario, the target areas extend... (Review)
Review
Manganese (Mn) exposure has evolved from acute, high-level exposure causing manganism to low, chronic lifetime exposure. In this latter scenario, the target areas extend beyond the globus pallidus (as seen with manganism) to the entire basal ganglia, including the substantia nigra pars compacta. This change of exposure paradigm has prompted numerous epidemiological investigations of the occurrence of Parkinson's disease (PD), or parkinsonism, due to the long-term impact of Mn. In parallel, experimental research has focused on the underlying pathogenic mechanisms of Mn and its interactions with genetic susceptibility. In this review, we provide evidence from both types of studies, with the aim to link the epidemiological data with the potential mechanistic interpretation.
Topics: Humans; Manganese; Parkinsonian Disorders; Parkinson Disease; Genetic Predisposition to Disease
PubMed: 37627255
DOI: 10.3390/biom13081190 -
Regenerative Therapy Dec 2022Parkinson's disease (PD) is the second most common progressive neurodegenerative disease, characterized by apoptosis of dopaminergic neurons in substansia nigra pars... (Review)
Review
Parkinson's disease (PD) is the second most common progressive neurodegenerative disease, characterized by apoptosis of dopaminergic neurons in substansia nigra pars compacta (SNpc) caused by ⍺-synuclein aggregation. The use of secretomes released by medicinal signaling cells (MSCs) is one the promising preventive approaches that target several mechanisms in the neuropathology of PD. Its components target the lack of neurotrophin factors, proteasome dysfunction, oxidative stress, mitochondrial dysfunction, and at last neuroinflammation via several pathways. The complex and obscure pathology of PD induce the difficulty of the search of potential preventive approach for this disease. We described the potential of secretome of MSC as the novel preventive approach for PD, especially by targeting the said major pathogenesis of PD.
PubMed: 36092507
DOI: 10.1016/j.reth.2022.08.003 -
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