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The FEBS Journal Oct 2018The cardinal motor symptoms of Parkinson's disease (PD) are caused by the death of dopaminergic neurons in the substantia nigra pars compacta (SNc). Alpha-synuclein... (Review)
Review
The cardinal motor symptoms of Parkinson's disease (PD) are caused by the death of dopaminergic neurons in the substantia nigra pars compacta (SNc). Alpha-synuclein (aSYN) pathology and mitochondrial dysfunction have been implicated in PD pathogenesis, but until recently it was unclear why SNc dopaminergic neurons should be particularly vulnerable to these two types of insult. In this brief review, the evidence that SNc dopaminergic neurons have an anatomical, physiological, and biochemical phenotype that predisposes them to mitochondrial dysfunction and synuclein pathology is summarized. The recognition that certain traits may predispose neurons to PD-linked pathology creates translational opportunities for slowing or stopping disease progression.
Topics: Animals; Calcium; Dopaminergic Neurons; Humans; Mitochondria; Oxidative Stress; Parkinson Disease; alpha-Synuclein
PubMed: 30028088
DOI: 10.1111/febs.14607 -
Development (Cambridge, England) Jun 2015Midbrain dopaminergic (mDA) neuron development has been an intense area of research during recent years. This is due in part to a growing interest in regenerative... (Review)
Review
Midbrain dopaminergic (mDA) neuron development has been an intense area of research during recent years. This is due in part to a growing interest in regenerative medicine and the hope that treatment for diseases affecting mDA neurons, such as Parkinson's disease (PD), might be facilitated by a better understanding of how these neurons are specified, differentiated and maintained in vivo. This knowledge might help to instruct efforts to generate mDA neurons in vitro, which holds promise not only for cell replacement therapy, but also for disease modeling and drug discovery. In this Primer, we will focus on recent developments in understanding the molecular mechanisms that regulate the development of mDA neurons in vivo, and how they have been used to generate human mDA neurons in vitro from pluripotent stem cells or from somatic cells via direct reprogramming. Current challenges and future avenues in the development of a regenerative medicine for PD will be identified and discussed.
Topics: Animals; Body Patterning; Dopaminergic Neurons; Gene Expression Regulation, Developmental; Humans; Mesencephalon; Models, Biological; Neurogenesis
PubMed: 26015536
DOI: 10.1242/dev.097394 -
Movement Disorders : Official Journal... Feb 2020
Review
Topics: Cellular Senescence; Disease Progression; Dopaminergic Neurons; Humans; Matrix Attachment Region Binding Proteins
PubMed: 31998985
DOI: 10.1002/mds.27978 -
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 -
Nature Reviews. Neuroscience Mar 2023The midbrain dopamine (mDA) system is composed of molecularly and functionally distinct neuron subtypes that mediate specific behaviours and are linked to various brain... (Review)
Review
The midbrain dopamine (mDA) system is composed of molecularly and functionally distinct neuron subtypes that mediate specific behaviours and are linked to various brain diseases. Considerable progress has been made in identifying mDA neuron subtypes, and recent work has begun to unveil how these neuronal subtypes develop and organize into functional brain structures. This progress is important for further understanding the disparate physiological functions of mDA neurons and their selective vulnerability in disease, and will ultimately accelerate therapy development. This Review discusses recent advances in our understanding of molecularly defined mDA neuron subtypes and their circuits, ranging from early developmental events, such as neuron migration and axon guidance, to their wiring and function, and future implications for therapeutic strategies.
Topics: Humans; Dopaminergic Neurons; Mesencephalon; Brain; Dopamine; Brain Diseases
PubMed: 36653531
DOI: 10.1038/s41583-022-00669-3 -
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 -
Genetics Aug 2021Parkinson's disease (PD) is primarily characterized by the loss of dopaminergic (DA) neurons in the brain. However, little is known about why DA neurons are selectively...
Parkinson's disease (PD) is primarily characterized by the loss of dopaminergic (DA) neurons in the brain. However, little is known about why DA neurons are selectively vulnerable to PD. To identify genes that are associated with DA neuron loss, we screened through 201 wild-caught populations of Drosophila melanogaster as part of the Drosophila Genetic Reference Panel. Here, we identify the top-associated genes containing single-nucleotide polymorphisms that render DA neurons vulnerable. These genes were further analyzed by using mutant analysis and tissue-specific knockdown for functional validation. We found that this loss of DA neurons caused progressive locomotor dysfunction in mutants and gene knockdown analysis. The identification of genes associated with the progressive loss of DA neurons should help to uncover factors that render these neurons vulnerable in PD, and possibly develop strategies to make these neurons more resilient.
Topics: Animals; Dopaminergic Neurons; Drosophila melanogaster; Genome, Insect; Locomotion; Parkinson Disease; Polymorphism, Single Nucleotide
PubMed: 34038543
DOI: 10.1093/genetics/iyab081 -
Movement Disorders : Official Journal... Dec 2022Large-scale genome-wide association studies (GWASs) have reported multiple risk variants for Parkinson's disease (PD). However, little is known about how these reported...
BACKGROUND
Large-scale genome-wide association studies (GWASs) have reported multiple risk variants for Parkinson's disease (PD). However, little is known about how these reported risk variants confer risk of PD.
OBJECTIVE
To nominate genes whose genetically regulated expression in dopaminergic neurons may have a causal role in PD.
METHODS
We conducted a two-sample Mendelian randomization (MR) study by integrating large-scale genome-wide associations and expression quantitative trait loci (eQTL) data from dopaminergic neurons.
RESULTS
MR analysis nominated 10 risk genes whose genetically regulated expression in dopaminergic neurons may have a causal role in PD. These MR significant genes include FAM200B, NDUFAF2, NUP42, SH3GL2, STX1B, CCDC189, KAT8, PRSS36, VAMP4, and ZSWIM7.
CONCLUSIONS
We report the first MR study of PD by using dopaminergic neuron-specific eQTL and nominate novel risk genes for PD. Further functional characterization of the nominated risk genes will provide mechanistic insights into PD pathogenesis and potential therapeutic targets. © 2022 International Parkinson and Movement Disorder Society.
Topics: Humans; Genome-Wide Association Study; Quantitative Trait Loci; Mendelian Randomization Analysis; Parkinson Disease; Dopaminergic Neurons; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide
PubMed: 36177513
DOI: 10.1002/mds.29239 -
Wiley Interdisciplinary Reviews.... 2015Midbrain dopaminergic neurons are involved in regulating motor control, reward behavior, and cognition. Degeneration or dysfunction of midbrain dopaminergic neurons is... (Review)
Review
UNLABELLED
Midbrain dopaminergic neurons are involved in regulating motor control, reward behavior, and cognition. Degeneration or dysfunction of midbrain dopaminergic neurons is implicated in several neuropsychiatric disorders such as Parkinson's disease, substance use disorders, depression, and schizophrenia. Understanding the developmental processes that generate midbrain dopaminergic neurons will facilitate the generation of dopaminergic neurons from stem cells for cell replacement therapies to substitute degenerating cells in Parkinson's disease patients and will forward our understanding on how functional diversity of dopaminergic neurons in the adult brain is established. Midbrain dopaminergic neurons develop in a multistep process. Following the induction of the ventral midbrain, a distinct dopaminergic progenitor domain is specified and dopaminergic progenitors undergo proliferation, neurogenesis, and differentiation. Subsequently, midbrain dopaminergic neurons acquire a mature dopaminergic phenotype, migrate to their final position and establish projections and connections to their forebrain targets. This review will discuss insights gained on the signaling network of secreted molecules, cell surface receptors, and transcription factors that regulate specification and differentiation of midbrain dopaminergic progenitors and neurons, from the induction of the ventral midbrain to the migration of dopaminergic neurons. For further resources related to this article, please visit the WIREs website.
CONFLICT OF INTEREST
The authors have declared no conflicts of interest for this article.
Topics: Animals; Cell Differentiation; Cell Movement; Dopaminergic Neurons; Humans; Mesencephalon; Neurogenesis; Stem Cells
PubMed: 25565353
DOI: 10.1002/wdev.169 -
Journal of Neurochemistry Oct 2016Developing new therapeutic strategies for Parkinson's disease requires cellular models. Current models reproduce the two most salient changes found in the brains of... (Review)
Review
Developing new therapeutic strategies for Parkinson's disease requires cellular models. Current models reproduce the two most salient changes found in the brains of patients with Parkinson's disease: The degeneration of dopaminergic neurons and the existence of protein aggregates consisting mainly of α-synuclein. Cultured cells offer many advantages over studying Parkinson's disease directly in patients or in animal models. At the same time, the choice of a specific cellular model entails the requirement to focus on one aspect of the disease while ignoring others. This article is intended for researchers planning to use cellular models for their studies. It describes for commonly used cell types the aspects of Parkinson's disease they model along with technical advantages and disadvantages. It might also be helpful for researchers from other fields consulting literature on cellular models of Parkinson's disease. Important models for the study of dopaminergic neuron degeneration include Lund human mesencephalic cells and primary neurons, and a case is made for the use of non-dopaminergic cells to model pathogenesis of non-motor symptoms of Parkinson's disease. With regard to α-synuclein aggregates, this article describes strategies to induce and measure aggregates with a focus on fluorescent techniques. Cellular models reproduce the two most salient changes of Parkinson's disease, the degeneration of dopaminergic neurons and the existence of α-synuclein aggregates. This article is intended for researchers planning to use cellular models for their studies. It describes for commonly used cell types and treatments the aspects of Parkinson's disease they model along with technical advantages and disadvantages. Furthermore, this article describes strategies to induce and measure aggregates with a focus on fluorescent techniques. This article is part of a special issue on Parkinson disease.
Topics: Animals; Cell Line, Tumor; Cells, Cultured; Disease Models, Animal; Dopaminergic Neurons; Humans; Parkinson Disease; Substantia Nigra; alpha-Synuclein
PubMed: 27091001
DOI: 10.1111/jnc.13618