-
Cells Dec 2020Parkinson's disease (PD) is the second most common neurodegenerative disease. PD patients exhibit motor symptoms such as akinesia/bradykinesia, tremor, rigidity, and... (Review)
Review
Parkinson's disease (PD) is the second most common neurodegenerative disease. PD patients exhibit motor symptoms such as akinesia/bradykinesia, tremor, rigidity, and postural instability due to a loss of nigrostriatal dopaminergic neurons. Although the pathogenesis in sporadic PD remains unknown, there is a consensus on the involvement of non-neuronal cells in the progression of PD pathology. Astrocytes are the most numerous glial cells in the central nervous system. Normally, astrocytes protect neurons by releasing neurotrophic factors, producing antioxidants, and disposing of neuronal waste products. However, in pathological situations, astrocytes are known to produce inflammatory cytokines. In addition, various studies have reported that astrocyte dysfunction also leads to neurodegeneration in PD. In this article, we summarize the interaction of astrocytes and dopaminergic neurons, review the pathogenic role of astrocytes in PD, and discuss therapeutic strategies for the prevention of dopaminergic neurodegeneration. This review highlights neuron-astrocyte interaction as a target for the development of disease-modifying drugs for PD in the future.
Topics: Animals; Antioxidants; Astrocytes; Disease Progression; Dopamine; Dopaminergic Neurons; Humans; Inflammation; Mitochondria; Nerve Degeneration; Neuroglia; Neurons; Neuroprotection; Oxidative Stress; Parkinson Disease; Signal Transduction; alpha-Synuclein
PubMed: 33297340
DOI: 10.3390/cells9122623 -
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 -
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 -
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 -
Cell Oct 2016Understanding human embryonic ventral midbrain is of major interest for Parkinson's disease. However, the cell types, their gene expression dynamics, and their... (Comparative Study)
Comparative Study
Understanding human embryonic ventral midbrain is of major interest for Parkinson's disease. However, the cell types, their gene expression dynamics, and their relationship to commonly used rodent models remain to be defined. We performed single-cell RNA sequencing to examine ventral midbrain development in human and mouse. We found 25 molecularly defined human cell types, including five subtypes of radial glia-like cells and four progenitors. In the mouse, two mature fetal dopaminergic neuron subtypes diversified into five adult classes during postnatal development. Cell types and gene expression were generally conserved across species, but with clear differences in cell proliferation, developmental timing, and dopaminergic neuron development. Additionally, we developed a method to quantitatively assess the fidelity of dopaminergic neurons derived from human pluripotent stem cells, at a single-cell level. Thus, our study provides insight into the molecular programs controlling human midbrain development and provides a foundation for the development of cell replacement therapies.
Topics: Animals; Cell Line; Cellular Reprogramming Techniques; Dopaminergic Neurons; Humans; Machine Learning; Mesencephalon; Mice; Neural Stem Cells; Neurogenesis; Neuroglia; Pluripotent Stem Cells; Sequence Analysis, RNA; Single-Cell Analysis
PubMed: 27716510
DOI: 10.1016/j.cell.2016.09.027 -
Cells Jan 2019Parkinson's Disease (PD) is an intractable disease resulting in localized neurodegeneration of dopaminergic neurons of the substantia nigra pars compacta. Many current... (Review)
Review
Parkinson's Disease (PD) is an intractable disease resulting in localized neurodegeneration of dopaminergic neurons of the substantia nigra pars compacta. Many current therapies of PD can only address the symptoms and not the underlying neurodegeneration of PD. To better understand the pathophysiological condition, researchers continue to seek models that mirror PD's phenotypic manifestations as closely as possible. Recent advances in the field of cellular reprogramming and personalized medicine now allow for previously unattainable cell therapies and patient-specific modeling of PD using induced pluripotent stem cells (iPSCs). iPSCs can be selectively differentiated into a dopaminergic neuron fate naturally susceptible to neurodegeneration. In iPSC models, unlike other artificially-induced models, endogenous cellular machinery and transcriptional feedback are preserved, a fundamental step in accurately modeling this genetically complex disease. In addition to accurately modeling PD, iPSC lines can also be established with specific genetic risk factors to assess genetic sub-populations' differing response to treatment. iPS cell lines can then be genetically corrected and subsequently transplanted back into the patient in hopes of re-establishing function. Current techniques focus on iPSCs because they are patient-specific, thereby reducing the risk of immune rejection. The year 2018 marked history as the year that the first human trial for PD iPSC transplantation began in Japan. This form of cell therapy has shown promising results in other model organisms and is currently one of our best options in slowing or even halting the progression of PD. Here, we examine the genetic contributions that have reshaped our understanding of PD, as well as the advantages and applications of iPSCs for modeling disease and personalized therapies.
Topics: Animals; Dopaminergic Neurons; Genetic Therapy; Humans; Induced Pluripotent Stem Cells; Models, Biological; Parkinson Disease; Precision Medicine
PubMed: 30621042
DOI: 10.3390/cells8010026 -
Nature Apr 2023The central amygdala (CeA) is implicated in a range of mental processes including attention, motivation, memory formation and extinction and in behaviours driven by...
The central amygdala (CeA) is implicated in a range of mental processes including attention, motivation, memory formation and extinction and in behaviours driven by either aversive or appetitive stimuli. How it participates in these divergent functions remains elusive. Here we show that somatostatin-expressing (Sst) CeA neurons, which mediate much of CeA functions, generate experience-dependent and stimulus-specific evaluative signals essential for learning. The population responses of these neurons in mice encode the identities of a wide range of salient stimuli, with the responses of separate subpopulations selectively representing the stimuli that have contrasting valences, sensory modalities or physical properties (for example, shock and water reward). These signals scale with stimulus intensity, undergo pronounced amplification and transformation during learning, and are required for both reward and aversive learning. Notably, these signals contribute to the responses of dopamine neurons to reward and reward prediction error, but not to their responses to aversive stimuli. In line with this, Sst CeA neuron outputs to dopamine areas are required for reward learning, but are dispensable for aversive learning. Our results suggest that Sst CeA neurons selectively process information about differing salient events for evaluation during learning, supporting the diverse roles of the CeA. In particular, the information for dopamine neurons facilitates reward evaluation.
Topics: Animals; Mice; Avoidance Learning; Central Amygdaloid Nucleus; Dopaminergic Neurons; Motivation; Reward; Neuronal Plasticity; Somatostatin; Electroshock
PubMed: 37020025
DOI: 10.1038/s41586-023-05910-2 -
Nature Neuroscience Jan 2022Social interactions are motivated behaviors that, in many species, facilitate learning. However, how the brain encodes the reinforcing properties of social interactions...
Social interactions are motivated behaviors that, in many species, facilitate learning. However, how the brain encodes the reinforcing properties of social interactions remains unclear. In this study, using in vivo recording in freely moving mice, we show that dopamine (DA) neurons of the ventral tegmental area (VTA) increase their activity during interactions with an unfamiliar conspecific and display heterogeneous responses. Using a social instrumental task, we then show that VTA DA neuron activity encodes social prediction error and drives social reinforcement learning. Thus, our findings suggest that VTA DA neurons are a neural substrate for a social learning signal that drives motivated behavior.
Topics: Animals; Dopaminergic Neurons; Mice; Reinforcement, Psychology; Reward; Social Interaction; Ventral Tegmental Area
PubMed: 34857949
DOI: 10.1038/s41593-021-00972-9 -
ELife Jun 2022New findings cast doubt on whether suppressing the RNA-binding protein PTBP1 can force astrocytes to become dopaminergic neurons.
New findings cast doubt on whether suppressing the RNA-binding protein PTBP1 can force astrocytes to become dopaminergic neurons.
Topics: Astrocytes; Cells, Cultured; Dopaminergic Neurons; Gatekeeping
PubMed: 35723428
DOI: 10.7554/eLife.80232 -
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