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Trends in Neurosciences Mar 2024Parkinson's disease (PD) is a neurodegenerative disease characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the... (Review)
Review
Parkinson's disease (PD) is a neurodegenerative disease characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the formation of Lewy bodies (LBs). The main proteinaceous component of LBs is aggregated α-synuclein (α-syn). However, the mechanisms underlying α-syn aggregation are not yet fully understood. Converging lines of evidence indicate that, under certain pathological conditions, various proteins can interact with α-syn and regulate its aggregation. Understanding these protein-protein interactions is crucial for unraveling the molecular mechanisms contributing to PD pathogenesis. In this review we provide an overview of the current knowledge on protein-protein interactions that regulate α-syn aggregation. Additionally, we briefly summarize the methods used to investigate the influence of protein-protein interactions on α-syn aggregation and propagation.
Topics: Humans; alpha-Synuclein; Dopaminergic Neurons; Neurodegenerative Diseases; Parkinson Disease
PubMed: 38355325
DOI: 10.1016/j.tins.2024.01.002 -
Regenerative Therapy Dec 2020Neurodegenerative disorders such as Parkinson's and Alzheimer's disease, are fundamental health concerns all around the world. The development of novel treatments and... (Review)
Review
Neurodegenerative disorders such as Parkinson's and Alzheimer's disease, are fundamental health concerns all around the world. The development of novel treatments and new techniques to address these disorders, are being actively studied by researchers and medical personnel. In the present review we will discuss the application of induced Pluripotent Stem Cells (iPSCs) for cell-therapy replacement and disease modelling. The aim of iPSCs is to restore the functionality of the damaged tissue by replacing the impaired cells with competitive ones. To achieve this objective, iPSCs can be properly differentiated into virtually any cell fate and can be strongly translated into human health via and disease modeling for the development of new therapies, the discovery of biomarkers for several disorders, the elaboration and testing of new drugs as novel treatments, and as a tool for personalized medicine.
PubMed: 33426236
DOI: 10.1016/j.reth.2020.11.006 -
ACS Chemical Neuroscience Jun 2023Parkinson's disease (PD) is the second most prevailing progressive disorder leading to neurodegeneration, typically in people above 65 years of age. Motor clinical... (Review)
Review
Parkinson's disease (PD) is the second most prevailing progressive disorder leading to neurodegeneration, typically in people above 65 years of age. Motor clinical manifestations of PD appear in a much later stage and include rigidity, tremors, akinesia, and gait dysfunction. There are also nonmotor symptoms like GI and olfactory dysfunction. However, they cannot be considered for diagnosis of the disease, as they are unspecific. PD pathogenesis is mainly characterized by deposits of inclusion bodies on dopaminergic (DA) neurons in substantia nigra pars compacta region (SNpc) of the brain. The major component of these inclusion bodies, are α-synuclein aggregates. α-Synuclein undergoes misfolding and oligomerization to form aggregates and fibrils. These aggregates gradually propagate PD pathology. Other prominent features of this pathological development include mitochondrial dysfunction, neuroinflammation, oxidative stress, and impaired autophagy. These all contribute to neuronal degeneration. Besides this, there are many underlying factors which influence these processes. These factors comprise molecular proteins and signaling cascades. In this review, we have listed out underexplored molecular targets that may aid in development of neoteric and advanced therapeutics.
Topics: Humans; Parkinson Disease; alpha-Synuclein; Pars Compacta; Dopaminergic Neurons; Brain
PubMed: 37227448
DOI: 10.1021/acschemneuro.3c00084 -
Experimental Neurology Dec 2023Parkinson's disease is a neurological disorder characterized by degeneration of midbrain dopamine neurons, which results in numerous adaptations in basal ganglia... (Review)
Review
Parkinson's disease is a neurological disorder characterized by degeneration of midbrain dopamine neurons, which results in numerous adaptations in basal ganglia circuits. Research over the past twenty-five years has identified that midbrain dopamine neurons of the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) co-release multiple other transmitters including glutamate and GABA, in addition to their canonical transmitter, dopamine. This review summarizes previous work characterizing neurotransmitter co-release from dopamine neurons, work examining potential changes in co-release dynamics that result in animal models of Parkinson's disease, and future opportunities for determining how dysfunction in co-release may contribute to circuit dysfunction in Parkinson's disease.
Topics: Animals; Parkinson Disease; Substantia Nigra; Ventral Tegmental Area; Synaptic Transmission; Dopaminergic Neurons; Neurotransmitter Agents
PubMed: 37802381
DOI: 10.1016/j.expneurol.2023.114562 -
Neurosciences (Riyadh, Saudi Arabia) Jan 2023Parkinson's disease (PD) is a progressive widespread neurodegenerative disorder affecting the brain. It is characterized by dopaminergic neuron degeneration in the... (Review)
Review
Parkinson's disease (PD) is a progressive widespread neurodegenerative disorder affecting the brain. It is characterized by dopaminergic neuron degeneration in the substantia nigra pars compacta (SNpc). Current therapeutic options ease the symptoms of PD; however, they have multiple undesirable effects and do not slow the disease progression. Exercise by itself has many positive impacts on general health. In this review, the positive impact of different forms of exercise were found to improve motor and non-motor symptoms in PD. Exercise effects is mediate by multiple mechanisms, including the upregulation of brain-derived neurotrophic factor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, and autophagy regulating proteins; and downregulates proinflammatory cytokines. In this review, the significance of exercise in PD, as well as in the prevention and maintenance of the disease was discussed. Many questions are left unanswered in this manuscript, including potential genetic factors underlying response to exercise. Therefore, further high-quality studies on humans are needed.
Topics: Humans; Animals; Parkinson Disease; Dopamine; Exercise; Dopaminergic Neurons; Disease Models, Animal
PubMed: 36617448
DOI: 10.17712/nsj.2023.1.20220105 -
Neuropathology : Official Journal of... Apr 2022Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive movement disability accompanied by non-motor symptoms. The neuropathology hallmark... (Review)
Review
Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive movement disability accompanied by non-motor symptoms. The neuropathology hallmark of PD is the loss of dopaminergic neurons predominantly in the substantia nigra pars compacta and the presence of intracellular inclusions termed Lewy bodies (LBs), which are mainly composed of α-synuclein (αSyn). Detailed staging based on the distribution and progression pattern of αSyn pathology in the postmortem brains of PD patients revealed correlation with the clinical phenotypes but not invariably. Cumulative evidence from cell and animal studies has implied that αSyn propagation contributes to the anatomical spread of αSyn pathology in the brain. Here, we recount the studies over the past two centuries on the anatomopathological foundations of PD documented. We also review studies on the structural analysis of αSyn and LBs, Braak staging of αSyn pathology, the cell-to-cell propagation of αSyn as well as αSyn fibril polymorphisms, which underlie the phenotypic differences in synucleinopathies.
Topics: Animals; Dopaminergic Neurons; Humans; Lewy Bodies; Neuropathology; Parkinson Disease; alpha-Synuclein
PubMed: 35362115
DOI: 10.1111/neup.12812 -
Biomedicines Jul 2021Parkinson's disease (PD) is the most common neurodegenerative movement disorder. The neuropathological hallmark of the disease is the loss of dopamine neurons of the... (Review)
Review
Parkinson's disease (PD) is the most common neurodegenerative movement disorder. The neuropathological hallmark of the disease is the loss of dopamine neurons of the substantia nigra pars compacta. The clinical manifestations of PD are bradykinesia, rigidity, resting tremors and postural instability. PD patients often display non-motor symptoms such as depression, anxiety, weakness, sleep disturbances and cognitive disorders. Although, in 90% of cases, PD has a sporadic onset of unknown etiology, highly penetrant rare genetic mutations in many genes have been linked with typical familial PD. Understanding the mechanisms behind the DA neuron death in these Mendelian forms may help to illuminate the pathogenesis of DA neuron degeneration in the more common forms of PD. A key step in the identification of the molecular pathways underlying DA neuron death, and in the development of therapeutic strategies, is the creation and characterization of animal models that faithfully recapitulate the human disease. In this review, we outline the current status of PD modeling using mouse, rat and non-mammalian models, focusing on animal models for autosomal recessive PD.
PubMed: 34356877
DOI: 10.3390/biomedicines9070812 -
Frontiers in Medicine 2021Parkinson's disease (PD), a neurodegenerative disorder characterized by distinct aging-independent loss of dopaminergic neurons in substantia nigra pars compacta (SNpc)... (Review)
Review
Parkinson's disease (PD), a neurodegenerative disorder characterized by distinct aging-independent loss of dopaminergic neurons in substantia nigra pars compacta (SNpc) region urging toward neuronal loss. Over the decade, various key findings from clinical perspective to molecular pathogenesis have aided in understanding the genetics with assorted genes related with PD. Subsequently, several pathways have been incriminated in the pathogenesis of PD, involving mitochondrial dysfunction, protein aggregation, and misfolding. On the other hand, the sporadic form of PD cases is found with no genetic linkage, which still remain an unanswered question? The exertion in ascertaining vulnerability factors in PD considering the genetic factors are to be further dissevered in the forthcoming decades with advancement in research studies. One of the major proponents behind the prognosis of PD is the pathogenic transmutation of aberrant alpha-synuclein protein into amyloid fibrillar structures, which actuates neurodegeneration. Alpha-synuclein, transcribed by SNCA gene is a neuroprotein found predominantly in brain. It is implicated in the modulation of synaptic vesicle transport and eventual release of neurotransmitters. Due to genetic mutations and other elusive factors, the alpha-synuclein misfolds into its amyloid form. Therefore, this review aims in briefing the molecular understanding of the alpha-synuclein associated with PD.
PubMed: 34733860
DOI: 10.3389/fmed.2021.736978 -
ENeurologicalSci Dec 2020Parkinson's disease (PD) is a complex multi-factorial neurodegenerative disorder where various altered metabolic pathways contribute to the progression of the disease.... (Review)
Review
Parkinson's disease (PD) is a complex multi-factorial neurodegenerative disorder where various altered metabolic pathways contribute to the progression of the disease. Tryptophan (TRP) is a major precursor in kynurenine pathway (KP) and it has been discussed in various studies that the metabolites quinolinic acid (QUIN) causes neurotoxicity and kynurenic acid (KYNA) acts as neuroprotectant respectively. More studies are also focused on the effects of other KP metabolites and its enzymes as it has an association with ageing and PD pathogenesis. Until now, very few studies have targeted the role of genetic mutations in abnormal KP metabolism in adverse conditions of PD. Therefore, the present review gives an updated research studies on KP in connection with PD. Moreover, the review emphasizes on the urge for the development of biomarkers and also this would be an initiative in generating an alternative therapeutic approach for PD.
PubMed: 33134567
DOI: 10.1016/j.ensci.2020.100270 -
Brain : a Journal of Neurology Dec 2023Although neuromelanin is a dark pigment characteristic of dopaminergic neurons in the human substantia nigra pars compacta, its potential role in the pathogenesis of...
Although neuromelanin is a dark pigment characteristic of dopaminergic neurons in the human substantia nigra pars compacta, its potential role in the pathogenesis of Parkinson's disease (PD) has often been neglected since most commonly used laboratory animals lack neuromelanin. Here we took advantage of adeno-associated viral vectors encoding the human tyrosinase gene for triggering a time-dependent neuromelanin accumulation within substantia nigra pars compacta dopaminergic neurons in macaques up to similar levels of pigmentation as observed in elderly humans. Furthermore, neuromelanin accumulation induced an endogenous synucleinopathy mimicking intracellular inclusions typically observed in PD together with a progressive degeneration of neuromelanin-expressing dopaminergic neurons. Moreover, Lewy body-like intracellular inclusions were observed in cortical areas of the frontal lobe receiving dopaminergic innervation, supporting a circuit-specific anterograde spread of endogenous synucleinopathy by permissive trans-synaptic templating. In summary, the conducted strategy resulted in the development and characterization of a new macaque model of PD matching the known neuropathology of this disorder with unprecedented accuracy. Most importantly, evidence is provided showing that intracellular aggregation of endogenous α-synuclein is triggered by neuromelanin accumulation, therefore any therapeutic approach intended to decrease neuromelanin levels may provide appealing choices for the successful implementation of novel PD therapeutics.
Topics: Animals; Humans; Aged; Synucleinopathies; Substantia Nigra; alpha-Synuclein; Parkinson Disease; Primates
PubMed: 37769648
DOI: 10.1093/brain/awad331