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Cell Reports Mar 2024The brain is spatially organized and contains unique cell types, each performing diverse functions and exhibiting differential susceptibility to neurodegeneration. This...
The brain is spatially organized and contains unique cell types, each performing diverse functions and exhibiting differential susceptibility to neurodegeneration. This is exemplified in Parkinson's disease with the preferential loss of dopaminergic neurons of the substantia nigra pars compacta. Using a Parkinson's transgenic model, we conducted a single-cell spatial transcriptomic and dopaminergic neuron translatomic analysis of young and old mouse brains. Through the high resolving capacity of single-cell spatial transcriptomics, we provide a deep characterization of the expression features of dopaminergic neurons and 27 other cell types within their spatial context, identifying markers of healthy and aging cells, spanning Parkinson's relevant pathways. We integrate gene enrichment and genome-wide association study data to prioritize putative causative genes for disease investigation, identifying CASR as a regulator of dopaminergic calcium handling. These datasets represent the largest public resource for the investigation of spatial gene expression in brain cells in health, aging, and disease.
Topics: Mice; Animals; Dopaminergic Neurons; Parkinson Disease; Transcriptome; Substantia Nigra; Genome-Wide Association Study; Aging; Gene Expression Profiling
PubMed: 38386560
DOI: 10.1016/j.celrep.2024.113784 -
CNS & Neurological Disorders Drug... 2024Reactive oxygen species (ROS)-induced oxidative stress triggers the vicious cycle leading to the degeneration of dopaminergic neurons in the nigra pars compacta. ROS... (Review)
Review
Reactive oxygen species (ROS)-induced oxidative stress triggers the vicious cycle leading to the degeneration of dopaminergic neurons in the nigra pars compacta. ROS produced during the metabolism of dopamine is immediately neutralized by the endogenous antioxidant defense system (EADS) under physiological conditions. Aging decreases the vigilance of EADS and makes the dopaminergic neurons more vulnerable to oxidative stress. As a result, ROS left over by EADS oxidize the dopamine-derived catechols and produces a number of reactive dopamine quinones, which are precursors to endogenous neurotoxins. In addition, ROS causes lipid peroxidation, uncoupling of the electron transport chain, and DNA damage, which lead to mitochondrial dysfunction, lysosomal dysfunction, and synaptic dysfunction. The mutations in genes such as DNAJC6, SYNJ1, SH3GL2, LRRK2, PRKN, and VPS35 caused by ROS have been associated with synaptic dysfunction and the pathogenesis of Parkinson's disease (PD). The available drugs that are used against PD can only delay the progression of the disease, but they produce various side effects. Through their antioxidant activity, flavonoids can substantiate the EADS of dopaminergic neurons and disrupt the vicious cycle incepted by oxidative stress. In this review, we show how the oxidative metabolism of dopamine generates ROS and dopamine-quinones, which then exert unrestrained OS, causing mutations in several genes involved in the proper functioning of mitochondrion, synapse, and lysosome. Besides, we also present some examples of approved drugs used for the treatment of PD, therapies in the clinical trial phase, and an update on the flavonoids that have been tested to boost the EADS of dopaminergic neurons.
Topics: Humans; Oxidative Stress; Antioxidants; Dopamine; Parkinson Disease; Animals; Dopaminergic Neurons; Reactive Oxygen Species
PubMed: 37303175
DOI: 10.2174/1871527322666230609141519 -
Trends in Neurosciences Jan 2017Parkinson's disease (PD) is recognized by the accumulation of α-synuclein within neurons. In contrast to the current ascending theory where α-synuclein would propagate... (Review)
Review
Parkinson's disease (PD) is recognized by the accumulation of α-synuclein within neurons. In contrast to the current ascending theory where α-synuclein would propagate from neuron to neuron, we now propose the threshold theory for PD based on evidence of parallel degeneration of both central nervous system (CNS) and peripheral nervous system (PNS) in PD. The functional threshold is lower for the emergence of early symptoms before the classical motor symptoms of PD. This is due to the larger functional reserve of the midbrain dopamine and integrated basal ganglia motor systems to control movement. This threshold theory better accounts for the current neurobiology of PD symptom progression compared to the hypothesis that the disease ascends from the PNS to the CNS as proposed by Braak's hypothesis.
Topics: Animals; Brain; Dopaminergic Neurons; Humans; Models, Neurological; Parkinson Disease
PubMed: 27894611
DOI: 10.1016/j.tins.2016.10.008 -
Brain Research Apr 2022Cuprizone (CPZ) is a copper-chelator and toxic to mitochondria. Recent studies have shown oligodendrocyte (OL) loss and demyelination along with dopamine (DA) increase...
Cuprizone (CPZ) is a copper-chelator and toxic to mitochondria. Recent studies have shown oligodendrocyte (OL) loss and demyelination along with dopamine (DA) increase and behavioral abnormalities in CPZ-exposed mice, demonstrating its application in schizophrenia research. This study examined effects of CPZ exposure on autonomous behavior and dopaminergic neurotransmission in larval zebra fish. CPZ exposure was found to reduce the swimming velocity of zebra fish thus decreased swimming distance during day and night time. Moreover, the treatment induced a movement response of zebra fish larvae reacting to light-on/off switch featured by swimming velocity increase and decrease during the first and second half of the light-on/off phase, respectively. But, it abolished responses of zebra fish to sound-on/off seen in Control group. HPLC analysis showed elevated DA levels in the zebra fish, no change in NE and 5-HT levels. Transcriptome analysis reported changes in gene expression related to dopaminergic synapse and oxidative phosphorylation in CPZ-exposed larvae relative to Control group. Of the gene expression changes, up-regulation of drd2a, drd2b, drd4a and drd4rs was confirmed by RT-PCR, although no difference existed between Control and CPZ groups in dopaminergic neuron numbers. These results demonstrated dopaminergic hyperactivity and locomotor deficit in CPZ-exposed zebra fish larvae, encouraging further application of this model in exploring neurotoxic effects of CPZ on mitochondria and dopaminergic neurotransmission in zebra fish.
Topics: Animals; Behavior, Animal; Cuprizone; Disease Models, Animal; Dopamine; Dopaminergic Neurons; Motor Activity; Synaptic Transmission; Zebrafish
PubMed: 35085574
DOI: 10.1016/j.brainres.2022.147802 -
Neurologia Mar 2019Parkinson's disease is a progressive neurodegenerative disorder characterised by a loss of dopaminergic neurons in the substantia nigra pars compacta, which results in a... (Review)
Review
INTRODUCTION
Parkinson's disease is a progressive neurodegenerative disorder characterised by a loss of dopaminergic neurons in the substantia nigra pars compacta, which results in a significant decrease in dopamine levels and consequent functional motor impairment.
DEVELOPMENT
Although its aetiology is not fully understood, several pathogenic mechanisms, including oxidative stress, have been proposed. Current therapeutic approaches are based on dopamine replacement drugs; these agents, however, are not able to stop or even slow disease progression. Novel therapeutic approaches aimed at acting on the pathways leading to neuronal dysfunction and death are under investigation.
CONCLUSIONS
In recent years, such natural molecules as polyphenols, alkaloids, and saponins have been shown to have a neuroprotective effect due to their antioxidant and anti-inflammatory properties. The aim of our review is to analyse the most relevant studies worldwide addressing the benefits of some phytochemicals used in in vitro models of Parkinson's disease.
Topics: Alkaloids; Animals; Dopaminergic Neurons; Humans; Neuroprotective Agents; Parkinson Disease; Phytochemicals; Polyphenols; Saponins
PubMed: 27342389
DOI: 10.1016/j.nrl.2016.04.018 -
Neurobiology of Disease Dec 2022Dopamine metabolism, alpha-synuclein pathology, and iron homeostasis have all been implicated as potential contributors to the unique vulnerability of substantia nigra... (Review)
Review
Interactions of dopamine, iron, and alpha-synuclein linked to dopaminergic neuron vulnerability in Parkinson's disease and Neurodegeneration with Brain Iron Accumulation disorders.
Dopamine metabolism, alpha-synuclein pathology, and iron homeostasis have all been implicated as potential contributors to the unique vulnerability of substantia nigra dopaminergic neurons which preferentially decline in Parkinson's disease and some rare neurodegenerative disorders with shared pathological features. However, the mechanisms contributing to disease progression and resulting in dopaminergic neuron loss in the substantia nigra are still not completely understood. Increasing evidence demonstrates that disrupted dopamine, alpha-synuclein, and/or iron pathways, when combined with the unique morphological, physiological, and metabolic features of this neuron population, may culminate in weakened resilience to multiple stressors. This review analyzes the involvement of each of these pathways in dopamine neuron physiology and function, and discusses how disrupted interplay of dopamine, alpha-synuclein, and iron pathways may synergize to promote pathology and drive the unique vulnerability to disease states. We suggest that elucidating the interactions of dopamine with iron and alpha-synuclein, and the role of dopamine metabolism in driving pathogenic phenotypes will be critical for developing therapeutics to prevent progression in diseases that show degeneration of nigral dopamine neurons such as Parkinson's disease and the rare family of disorders known as Neurodegeneration with Brain Iron Accumulation.
Topics: Humans; alpha-Synuclein; Dopaminergic Neurons; Parkinson Disease; Dopamine; Iron; Substantia Nigra; Brain
PubMed: 36351559
DOI: 10.1016/j.nbd.2022.105920 -
Ageing Research Reviews Sep 2022Parkinson's disease (PD) is the second-most-common neurodegenerative disease characterized by motor and non-motor dysfunctions, which currently affects about 10 million... (Review)
Review
Parkinson's disease (PD) is the second-most-common neurodegenerative disease characterized by motor and non-motor dysfunctions, which currently affects about 10 million people worldwide. Gradual death and progressive loss of dopaminergic neurons in the pars compacta region of substantia nigra result in striatal dopamine deficiency in PD. Specific mutation with further aggregation of α-synuclein in the intraneuronal inclusion bodies is considered the neuropathological hallmark of this disease. PD is often associated with various organelle dysfunctions inside a dopaminergic neuron, including mitochondrial damage, proteasomal impairment, and production of reactive oxygen species, thus causing subsequent neuronal death. Apart from several genetic and non-genetic risk factors, emerging research establishes an association between cardiovascular diseases, including coronary heart disease, myocardial infarction, congestive heart failure, and ischemic stroke with PD. The majority of these cardiovascular diseases have an origin from atherosclerosis, where endothelial dysfunction following thrombus formation is significantly regulated by blood platelet. This non-nucleated cell fragment expresses not only neuron-specific molecules and receptors but also several PD-specific biomarkers such as α-synuclein, parkin, PTEN-induced kinase-1, tyrosine hydroxylase, dopamine transporter, thus making platelet a suitable peripheral model for PD. Besides its similarity with a dopaminergic neuron, platelet structural alterations, as well as functional abnormalities, are also evident in PD. However, the molecular mechanism behind platelet dysfunction is still elusive and quite controversial. This state-of-the-art review describes the detailed mechanism of platelet impairment in PD, addressing the novel platelet-associated therapeutic drug candidates for plausible PD management.
Topics: Blood Platelets; Cardiovascular Diseases; Dopaminergic Neurons; Humans; Neurodegenerative Diseases; Parkinson Disease; Precision Medicine; Substantia Nigra; alpha-Synuclein
PubMed: 35798236
DOI: 10.1016/j.arr.2022.101681 -
International Journal of Molecular... Apr 2024The etiology underlying most sporadic Parkinson's' disease (PD) cases is unknown. Environmental exposures have been suggested as putative causes of the disease. In cell... (Review)
Review
The etiology underlying most sporadic Parkinson's' disease (PD) cases is unknown. Environmental exposures have been suggested as putative causes of the disease. In cell models and in animal studies, certain chemicals can destroy dopaminergic neurons. However, the mechanisms of how these chemicals cause the death of neurons is not understood. Several of these agents are mitochondrial toxins that inhibit the mitochondrial complex I of the electron transport chain. Familial PD genes also encode proteins with important functions in mitochondria. Mitochondrial dysfunction of the respiratory chain, in combination with the presence of redox active dopamine molecules in these cells, will lead to the accumulation of reactive oxygen species (ROS) in dopaminergic neurons. Here, I propose a mechanism regarding how ROS may lead to cell killing with a specificity for neurons. One rarely considered hypothesis is that ROS produced by defective mitochondria will lead to the formation of oxidative DNA damage in nuclear DNA. Many genes that encode proteins with neuron-specific functions are extraordinary long, ranging in size from several hundred kilobases to well over a megabase. It is predictable that such long genes will contain large numbers of damaged DNA bases, for example in the form of 8-oxoguanine (8-oxoG), which is a major DNA damage type produced by ROS. These DNA lesions will slow down or stall the progression of RNA polymerase II, which is a term referred to as transcription stress. Furthermore, ROS-induced DNA damage may cause mutations, even in postmitotic cells such as neurons. I propose that the impaired transcription and mutagenesis of long, neuron-specific genes will lead to a loss of neuronal integrity, eventually leading to the death of these cells during a human lifetime.
Topics: Humans; Parkinson Disease; DNA Damage; Animals; Reactive Oxygen Species; Dopaminergic Neurons; Mitochondria; Oxidative Stress
PubMed: 38673772
DOI: 10.3390/ijms25084187 -
International Journal of Molecular... Feb 2018Mitochondria are important organelles in virtually all eukaryotic cells, and are involved in a wide range of physiological and pathophysiological processes. Besides the... (Review)
Review
Mitochondria are important organelles in virtually all eukaryotic cells, and are involved in a wide range of physiological and pathophysiological processes. Besides the generation of cellular energy in the form of adenosine triphosphate, mitochondria are also involved in calcium homeostasis, reactive oxygen species production and the activation of the intrinsic cell death pathway, thus determining cell survival and death. Mitochondrial abnormalities have been implicated in a wide range of disorders, including neurodegenerative disease such as Parkinson's disease (PD), and considered as a primary cause and central event responsible for the progressive loss of dopaminergic neurons in PD. Thus, reversion or attenuation of mitochondrial dysfunction should alleviate the severity or progression of the disease. The present review systematically summarizes the possible mechanisms associated with mitochondria‑mediated dopaminergic neuron damage in PD, in an attempt to elucidate the requirement for further studies for the development of effective PD treatments.
Topics: Calcium; Cell Death; Dopaminergic Neurons; Humans; Mitochondria; Parkinson Disease; Reactive Oxygen Species; Signal Transduction
PubMed: 29207041
DOI: 10.3892/ijmm.2017.3255 -
European Journal of Neurology Feb 2024The role of GGC repeat expansions within NOTCH2NLC in Parkinson's disease (PD) and the substantia nigra (SN) dopaminergic neuron remains unclear. Here, we profile the...
BACKGROUND AND PURPOSE
The role of GGC repeat expansions within NOTCH2NLC in Parkinson's disease (PD) and the substantia nigra (SN) dopaminergic neuron remains unclear. Here, we profile the NOTCH2NLC GGC repeat expansions in a large cohort of patients with PD. We also investigate the role of GGC repeat expansions within NOTCH2NLC in the dopaminergic neurodegeneration of SN.
METHODS
A total of 2,522 patients diagnosed with PD and 1,085 health controls were analyzed for the repeat expansions of NOTCH2NLC by repeat-primed PCR and GC-rich PCR assay. Furthermore, the effects of GGC repeat expansions in NOTCH2NLC on dopaminergic neurons were investigated by using recombinant adeno-associated virus (AAV)-mediated overexpression of NOTCH2NLC with 98 GGC repeats in the SN of mice by stereotactic injection.
RESULTS
Four PD pedigrees (4/333, 1.2%) and three sporadic PD patients (3/2189, 0.14%) were identified with pathogenic GGC repeat expansions (larger than 60 GGC repeats) in the NOTCH2NLC gene, while eight PD patients and one healthy control were identified with intermediate GGC repeat expansions ranging from 41 to 60 repeats. No significant difference was observed in the distribution of intermediate NOTCH2NLC GGC repeat expansions between PD cases and controls (Fisher's exact test p-value = 0.29). Skin biopsy showed P62-positive intranuclear NOTCH2NLC-polyGlycine (polyG) inclusions in the skin nerve fibers of patient. Expanded GGC repeats in NOTCH2NLC produced widespread intranuclear and perinuclear polyG inclusions, which led to a severe loss of dopaminergic neurons in the SN. Consistently, polyG inclusions were presented in the SN of EIIa-NOTCH2NLC-(GGC)98 transgenic mice and also led to dopaminergic neuron loss in the SN.
CONCLUSIONS
Overall, our findings provide strong evidence that GGC repeat expansions within NOTCH2NLC contribute to the pathogenesis of PD and cause degeneration of nigral dopaminergic neurons.
Topics: Animals; Humans; Mice; Dopaminergic Neurons; Intranuclear Inclusion Bodies; Mice, Transgenic; Nerve Degeneration; Parkinson Disease; Substantia Nigra; Trinucleotide Repeat Expansion
PubMed: 37975799
DOI: 10.1111/ene.16145