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Redox Biology Sep 2020Oxidative stress and inflammation have long been recognized to contribute to Parkinson's disease (PD), a common movement disorder characterized by the selective loss of... (Review)
Review
Oxidative stress and inflammation have long been recognized to contribute to Parkinson's disease (PD), a common movement disorder characterized by the selective loss of midbrain dopaminergic neurons (mDAn) of the substantia nigra pars compacta (SNpc). The causes and mechanisms still remain elusive, but a complex interplay between several genes and a number of interconnected environmental factors, are chiefly involved in mDAn demise, as they intersect the key cellular functions affected in PD, such as the inflammatory response, mitochondrial, lysosomal, proteosomal and autophagic functions. Nuclear factor erythroid 2 -like 2 (NFE2L2/Nrf2), the master regulator of cellular defense against oxidative stress and inflammation, and Wingless (Wnt)/β-catenin signaling cascade, a vital pathway for mDAn neurogenesis and neuroprotection, emerge as critical intertwinned actors in mDAn physiopathology, as a decline of an Nrf2/Wnt/β-catenin prosurvival axis with age underlying PD mutations and a variety of noxious environmental exposures drive PD neurodegeneration. Unexpectedly, astrocytes, the so-called "star-shaped" cells, harbouring an arsenal of "beneficial" and "harmful" molecules represent the turning point in the physiopathological and therapeutical scenario of PD. Fascinatingly, "astrocyte's fil rouge" brings back to Nrf2/Wnt resilience, as boosting the Nrf2/Wnt resilience program rejuvenates astrocytes, in turn (i) mitigating nigrostriatal degeneration of aged mice, (ii) reactivating neural stem progenitor cell proliferation and neuron differentiation in the brain and (iii) promoting a beneficial immunomodulation via bidirectional communication with mDAns. Then, through resilience of Nrf2/Wnt/β-catenin anti-ageing, prosurvival and proregenerative molecular programs, it seems possible to boost the inherent endogenous self-repair mechanisms. Here, the cellular and molecular aspects as well as the therapeutical options for rejuvenating glia-neuron dialogue will be discussed together with major glial-derived mechanisms and therapies that will be fundamental to the identification of novel diagnostic tools and treatments for neurodegenerative diseases (NDs), to fight ageing and nigrostriatal DAergic degeneration and promote functional recovery.
Topics: Animals; Dopaminergic Neurons; Mice; NF-E2-Related Factor 2; Neuroglia; Parkinson Disease; Rejuvenation
PubMed: 32863224
DOI: 10.1016/j.redox.2020.101664 -
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 -
International Journal of Molecular... Oct 2021Parkinson's disease (PD) is a slowly progressive multisystem disorder affecting dopaminergic neurons of the substantia nigra pars compacta (SNpc), which is characterized... (Review)
Review
Parkinson's disease (PD) is a slowly progressive multisystem disorder affecting dopaminergic neurons of the substantia nigra pars compacta (SNpc), which is characterized by a decrease of dopamine (DA) in their striatal terminals. Treatment of PD with levodopa or DA receptor agonists replaces the function of depleted DA in the striatum. Prolonged treatment with these agents often has variable therapeutic effects and leads to the development of undesirable dyskinesia. Consequently, a crucial unmet demand in the management of Parkinson's disease is the discovery of new approaches that could slow down, stop, or reverse the process of neurodegeneration. Novel potential treatments involving natural substances with neuroprotective activities are being developed. Curcumin is a polyphenolic compound isolated from the rhizomes of Curcuma longa (turmeric). It has been demonstrated to have potent anti-inflammatory, antioxidant, free radical scavenging, mitochondrial protecting, and iron-chelating effects, and is considered a promising therapeutic and nutraceutical agent for the treatment of PD. However, molecular and cellular mechanisms that mediate the pharmacological actions of curcumin remain largely unknown. Stimulation of nicotinic receptors and, more precisely, selective α7 nicotinic acetylcholine receptors (α7-nAChR), have been found to play a major modulatory role in the immune system via the "cholinergic anti-inflammatory pathway". Recently, α7-nAChR has been proposed to be a potential therapeutic approach in PD. In this review, the detailed mechanisms of the neuroprotective activities of curcumin as a potential therapeutic agent to help Parkinson's patients are being discussed and elaborated on in detail.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Curcumin; Humans; Neuroprotective Agents; Parkinson Disease
PubMed: 34681908
DOI: 10.3390/ijms222011248 -
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 -
JCI Insight Jan 2024Circadian rhythm dysfunction is a hallmark of Parkinson disease (PD), and diminished expression of the core clock gene Bmal1 has been described in patients with PD....
Circadian rhythm dysfunction is a hallmark of Parkinson disease (PD), and diminished expression of the core clock gene Bmal1 has been described in patients with PD. BMAL1 is required for core circadian clock function but also serves nonrhythmic functions. Germline Bmal1 deletion can cause brain oxidative stress and synapse loss in mice, and it can exacerbate dopaminergic neurodegeneration in response to the toxin MPTP. Here we examined the effect of cell type-specific Bmal1 deletion on dopaminergic neuron viability in vivo. We observed that global, postnatal deletion of Bmal1 caused spontaneous loss of tyrosine hydroxylase+ (TH+) dopaminergic neurons in the substantia nigra pars compacta (SNpc). This was not replicated by light-induced disruption of behavioral circadian rhythms and was not induced by astrocyte- or microglia-specific Bmal1 deletion. However, either pan-neuronal or TH neuron-specific Bmal1 deletion caused cell-autonomous loss of TH+ neurons in the SNpc. Bmal1 deletion did not change the percentage of TH neuron loss after α-synuclein fibril injection, though Bmal1-KO mice had fewer TH neurons at baseline. Transcriptomics analysis revealed dysregulation of pathways involved in oxidative phosphorylation and Parkinson disease. These findings demonstrate a cell-autonomous role for BMAL1 in regulating dopaminergic neuronal survival and may have important implications for neuroprotection in PD.
Topics: Animals; Humans; Mice; ARNTL Transcription Factors; Circadian Clocks; Dopamine; Dopaminergic Neurons; Mice, Knockout; Parkinson Disease
PubMed: 38032732
DOI: 10.1172/jci.insight.162771 -
Neuropharmacology Jan 2022Parkinson's disease (PD) is the second most common neurodegenerative disorder and is defined pathologically by the abnormal accumulation of the presynaptic protein... (Review)
Review
Parkinson's disease (PD) is the second most common neurodegenerative disorder and is defined pathologically by the abnormal accumulation of the presynaptic protein alpha-synuclein (aSyn) in the form of Lewy bodies and Lewy neurites and loss of midbrain dopaminergic neurons in the substantia nigra pars compacta. Because of aSyn's involvement in both sporadic and familial forms of PD, it has become a key target for the development of novel therapeutics. Aberrant aSyn is associated with multiple mechanisms of neuronal dysfunction and degeneration including inflammation, impaired mitochondrial function, altered protein degradation systems, and oxidative stress. Inflammation, in particular, has emerged as a potential significant contributor early in the disease making it an attractive target for disease modification and neuroprotection. Thus, immunotherapies targeting aSyn are currently being investigated in pre-clinical and clinical trials. The focus of this review is to highlight the role of aSyn in neuroinflammation and discuss the current status of aSyn-directed immunotherapies in pre-clinical and clinical trials for PD.
Topics: Animals; Clinical Trials as Topic; Dopaminergic Neurons; Humans; Immune System; Immunotherapy; Immunotherapy, Active; Lewy Bodies; Mice, Transgenic; Molecular Targeted Therapy; Neuroinflammatory Diseases; Oxidative Stress; Parkinson Disease; Substantia Nigra; alpha-Synuclein
PubMed: 34742741
DOI: 10.1016/j.neuropharm.2021.108870 -
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 -
Neurologia Sep 2020Parkinson's disease (PD) is the second most common neurodegenerative disorder. It is characterised by selective loss of dopaminergic neurons in the substantia nigra pars... (Review)
Review
INTRODUCTION
Parkinson's disease (PD) is the second most common neurodegenerative disorder. It is characterised by selective loss of dopaminergic neurons in the substantia nigra pars compacta, which results in dopamine depletion, leading to a number of motor and non-motor symptoms.
DEVELOPMENT
In recent years, the development of new animal models using nuclease-based genome-editing technology (ZFN, TALEN, and CRISPR/Cas9 nucleases) has enabled the introduction of custom-made modifications into the genome to replicate key features of PD, leading to significant advances in our understanding of the pathophysiology of the disease.
CONCLUSIONS
We review the most recent studies on this new generation of in vitro and in vivo PD models, which replicate the most relevant symptoms of the disease and enable better understanding of the aetiology and mechanisms of PD. This may be helpful in the future development of effective treatments to halt or slow disease progression.
Topics: Animals; Animals, Genetically Modified; CRISPR-Cas Systems; Disease Models, Animal; Gene Editing; Humans; Parkinson Disease; Technology; Transcription Factors; Zinc Finger Nucleases
PubMed: 29196142
DOI: 10.1016/j.nrl.2017.08.009 -
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