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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (20 March 2023) | Viewed by 32760

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Dr. Yasemin M. Akay

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Department of Biomedical Engineering, University of Houston, Houston, TX 77204-5060, USA
Interests: coronary artery disease; stent; noninvasive monitoring; nonlinear dynamics analysis; approximate entropy; 3D co-culture; glioblastoma; astrocytes; tumor microenvironment; PEGDA; addiction; cancer research; data science in medicine
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Dear Colleagues,

Dopaminergic neurons located in the mammalian ventral midbrain have attracted the attention of many biomedical researchers due to their effect in severe human neuropsychiatric and neurodegenerative disorders. There are four major signalling pathways which play critical roles during the development of the midbrain dopaminergic (mDA) neurons. In spite of the intense research conducted in recent years, we have achieved little understanding related to the crosstalk and the interaction between those four major signalling pathways and how they promote the development of mDA neurons in the mammalian embryo. This has been a very exciting research field and a number of questions remain answering:

(1) Which cellular and molecular mechanisms constitute the basis for the programming of the development of VTA DA neurons versus SNc DA neurons in vivo?

2) What could be the explanation for the vulnerability of some types of mDA neurons in some neurodegenerative disorders?

(3) What will be the efficacy and safety outcomes of the clinical trials using human stem cell-derived mDA neurons?

Contributions to this Special Issue will provide new insights into the mechanisms of action of the development of DA neurons and for the modelling and drug screening of the disorders mentioned above in the basic and clinical research.

Due to the success of the 1st edition, we would like to add more results and new insights from recent research projects. You can find the 1st edition at the following link: https://www.mdpi.com/journal/ijms/special_issues/dopaminergic_neurons

Dr. Yasemin M. Akay
Guest Editor

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

neuron
dopamine
mDA
signalling pathways
human stem cell

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Related Special Issues

Development of Dopaminergic Neurons in International Journal of Molecular Sciences (9 articles)
Development of Dopaminergic Neurons 3.0 in International Journal of Molecular Sciences (6 articles)

Published Papers (12 papers)

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Research

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19 pages, 5651 KiB

Open AccessArticle

HDAC6 Deficiency Has Moderate Effects on Behaviors and Parkinson’s Disease Pathology in Mice

by Jiayin Zhao, Yongtao He, Yufei Duan, Yuanyuan Ma, Hongtian Dong, Xiaoshuang Zhang, Rong Fang, Yunhe Zhang, Mei Yu and Fang Huang

Int. J. Mol. Sci. 2023, 24(12), 9975; https://doi.org/10.3390/ijms24129975 - 9 Jun 2023

Viewed by 2047

Abstract

Histone deacetylase 6 (HDAC6) is involved in the regulation of protein aggregation and neuroinflammation, but its role in Parkinson’s disease (PD) remains controversial. In this study, Hdac6^−/− mice were generated by CRISPR-Cas9 technology for exploring the effect of HDAC6 on the pathological progression of PD. We found that male Hdac6^−/− mice exhibit hyperactivity and certain anxiety. In the acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice, though motor injury was slightly alleviated by HDAC6 deficiency, dopamine (DA) depletion in the striatum, the decrease in the number of DA neurons in the substantia nigra (SN) and the reduction in DA neuronal terminals were not affected. In addition, activation of glial cells and the expression of α-synuclein, as well as the levels of apoptosis-related proteins in the nigrostriatal pathway, were not changed in MPTP-injected wild-type and Hdac6^−/− mice. Therefore, HDAC6 deficiency leads to moderate alterations of behaviors and Parkinson’s disease pathology in mice. Full article

(This article belongs to the Special Issue Development of Dopaminergic Neurons 2.0)

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21 pages, 4853 KiB

Open AccessArticle

Multi-Region Microdialysis Imaging Platform Revealed Dorsal Raphe Nucleus Calcium Signaling and Serotonin Dynamics during Nociceptive Pain

by Latiful Akbar, Virgil Christian Garcia Castillo, Joshua Philippe Olorocisimo, Yasumi Ohta, Mamiko Kawahara, Hironari Takehara, Makito Haruta, Hiroyuki Tashiro, Kiyotaka Sasagawa, Masahiro Ohsawa, Yasemin M. Akay, Metin Akay and Jun Ohta

Int. J. Mol. Sci. 2023, 24(7), 6654; https://doi.org/10.3390/ijms24076654 - 3 Apr 2023

Cited by 8 | Viewed by 2684

Abstract

In this research, we combined our ultralight micro-imaging device for calcium imaging with microdialysis to simultaneously visualize neural activity in the dorsal raphe nucleus (DRN) and measure serotonin release in the central nucleus of the amygdala (CeA) and the anterior cingulate cortex (ACC). Using this platform, we observed brain activity following nociception induced by formalin injection in the mouse’s hind paw. Our device showed that DRN fluorescence intensity increased after formalin injection, and the increase was highly correlated with the elevation in serotonin release in both the CeA and ACC. The increase in calcium fluorescence intensity occurred during the acute and inflammatory phases, which suggests the biphasic response of nociceptive pain. Furthermore, we found that the increase in fluorescence intensity was positively correlated with mouse licking behavior. Lastly, we compared the laterality of pain stimulation and found that DRN fluorescence activity was higher for contralateral stimulation. Microdialysis showed that CeA serotonin concentration increased only after contralateral stimulation, while ACC serotonin release responded bilaterally. In conclusion, our study not only revealed the inter-regional serotonergic connection among the DRN, the CeA, and the ACC, but also demonstrated that our device is feasible for multi-site implantation in conjunction with a microdialysis system, allowing the simultaneous multi-modal observation of different regions in the brain. Full article

(This article belongs to the Special Issue Development of Dopaminergic Neurons 2.0)

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12 pages, 1982 KiB

Open AccessArticle

The Influence of Prenatal Exposure to Methamphetamine on the Development of Dopaminergic Neurons in the Ventral Midbrain

by Walaa F. Alsanie, Sherin Abdelrahman, Raed I. Felimban, Heba A. Alkhatabi, Ahmed Gaber, Ebtisam Abdulah Alosimi, Majid Alhomrani, Hamza Habeeballah, Charlotte A. E. Hauser, Abdulhakeem S. Alamri, Aiysha Althobaiti, Abdulaziz Alsharif, Ahmed S. Alzahrani, Mohammad S. Al-Ghamdi, Bassem M. Raafat, Khaled A. Alswat, Yusuf S. Althobaiti and Yousif A. Asiri

Int. J. Mol. Sci. 2023, 24(6), 5668; https://doi.org/10.3390/ijms24065668 - 16 Mar 2023

Cited by 4 | Viewed by 2255

Abstract

Methamphetamine, a highly addictive central nervous system (CNS) stimulant, is used worldwide as an anorexiant and attention enhancer. Methamphetamine use during pregnancy, even at therapeutic doses, may harm fetal development. Here, we examined whether exposure to methamphetamine affects the morphogenesis and diversity of ventral midbrain dopaminergic neurons (VMDNs). The effects of methamphetamine on morphogenesis, viability, the release of mediator chemicals (such as ATP), and the expression of genes involved in neurogenesis were evaluated using VMDNs isolated from the embryos of timed-mated mice on embryonic day 12.5. We demonstrated that methamphetamine (10 µM; equivalent to its therapeutic dose) did not affect the viability and morphogenesis of VMDNs, but it reduced the ATP release negligibly. It significantly downregulated Lmx1a, En1, Pitx3, Th, Chl1, Dat, and Drd1 but did not affect Nurr1 or Bdnf expression. Our results illustrate that methamphetamine could impair VMDN differentiation by altering the expression of important neurogenesis-related genes. Overall, this study suggests that methamphetamine use may impair VMDNs in the fetus if taken during pregnancy. Therefore, it is essential to exercise strict caution for its use in expectant mothers. Full article

(This article belongs to the Special Issue Development of Dopaminergic Neurons 2.0)

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15 pages, 3651 KiB

Open AccessArticle

Upregulation of DJ-1 in Dopaminergic Neurons by a Physically-Modified Saline: Implications for Parkinson’s Disease

by Malabendu Jana, Sridevi Dasarathy, Supurna Ghosh and Kalipada Pahan

Int. J. Mol. Sci. 2023, 24(5), 4652; https://doi.org/10.3390/ijms24054652 - 28 Feb 2023

Cited by 2 | Viewed by 1946

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disorder in human and loss-of-functions DJ-1 mutations are associated with a familial form of early onset PD. Functionally, DJ-1 (PARK7), a neuroprotective protein, is known to support mitochondria and protect cells from oxidative stress. Mechanisms and agents by which the level of DJ-1 could be increased in the CNS are poorly described. RNS60 is a bioactive aqueous solution created by exposing normal saline to Taylor-Couette-Poiseuille flow under high oxygen pressure. Recently we have described neuroprotective, immunomodulatory and promyelinogenic properties of RNS60. Here we delineate that RNS60 is also capable of increasing the level of DJ-1 in mouse MN9D neuronal cells and primary dopaminergic neurons, highlighting another new neuroprotective effect of RNS60. While investigating the mechanism we found the presence of cAMP response element (CRE) in DJ-1 gene promoter and stimulation of CREB activation in neuronal cells by RNS60. Accordingly, RNS60 treatment increased the recruitment of CREB to the DJ-1 gene promoter in neuronal cells. Interestingly, RNS60 treatment also induced the enrollment of CREB-binding protein (CBP), but not the other histone acetyl transferase p300, to the promoter of DJ-1 gene. Moreover, knockdown of CREB by siRNA led to the inhibition of RNS60-mediated DJ-1 upregulation, indicating an important role of CREB in DJ-1 upregulation by RNS60. Together, these results indicate that RNS60 upregulates DJ-1 in neuronal cells via CREB–CBP pathway. It may be of benefit for PD and other neurodegenerative disorders. Full article

(This article belongs to the Special Issue Development of Dopaminergic Neurons 2.0)

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25 pages, 12683 KiB

Open AccessArticle

Nicotine-Mediated Recruitment of GABAergic Neurons to a Dopaminergic Phenotype Attenuates Motor Deficits in an Alpha-Synuclein Parkinson’s Model

by Jessica IChi Lai, Alessandra Porcu, Benedetto Romoli, Maria Keisler, Fredric P. Manfredsson, Susan B. Powell and Davide Dulcis

Int. J. Mol. Sci. 2023, 24(4), 4204; https://doi.org/10.3390/ijms24044204 - 20 Feb 2023

Cited by 7 | Viewed by 2921

Abstract

Previous work revealed an inverse correlation between tobacco smoking and Parkinson’s disease (PD) that is associated with nicotine-induced neuroprotection of dopaminergic (DA) neurons against nigrostriatal damage in PD primates and rodent models. Nicotine, a neuroactive component of tobacco, can directly alter the activity of midbrain DA neurons and induce non-DA neurons in the substantia nigra (SN) to acquire a DA phenotype. Here, we investigated the recruitment mechanism of nigrostriatal GABAergic neurons to express DA phenotypes, such as transcription factor Nurr1 and DA-synthesizing enzyme tyrosine hydroxylase (TH), and the concomitant effects on motor function. Wild-type and α-syn-overexpressing (PD) mice treated with chronic nicotine were assessed by behavioral pattern monitor (BPM) and immunohistochemistry/in situ hybridization to measure behavior and the translational/transcriptional regulation of neurotransmitter phenotype following selective Nurr1 overexpression or DREADD-mediated chemogenetic activation. We found that nicotine treatment led to a transcriptional TH and translational Nurr1 upregulation within a pool of SN GABAergic neurons in wild-type animals. In PD mice, nicotine increased Nurr1 expression, reduced the number of α-syn-expressing neurons, and simultaneously rescued motor deficits. Hyperactivation of GABA neurons alone was sufficient to elicit de novo translational upregulation of Nurr1. Retrograde labeling revealed that a fraction of these GABAergic neurons projects to the dorsal striatum. Finally, concomitant depolarization and Nurr1 overexpression within GABA neurons were sufficient to mimic nicotine-mediated dopamine plasticity. Revealing the mechanism of nicotine-induced DA plasticity protecting SN neurons against nigrostriatal damage could contribute to developing new strategies for neurotransmitter replacement in PD. Full article

(This article belongs to the Special Issue Development of Dopaminergic Neurons 2.0)

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13 pages, 2331 KiB

Open AccessArticle

Investigating the Modulation of the VTA Neurons in Nicotine-Exposed Pups during Early Maturation Using Optogenetics

by Austin Ganaway, Yoshinori Sunaga, Yasumi Ohta, Jun Ohta, Metin Akay and Yasemin M. Akay

Int. J. Mol. Sci. 2023, 24(3), 2280; https://doi.org/10.3390/ijms24032280 - 23 Jan 2023

Cited by 1 | Viewed by 1948

Abstract

Advancing the understanding of the relationship between perinatal nicotine addiction and the reward mechanism of the brain is crucial for uncovering and implementing new treatments for addiction control and prevention. The mesolimbic pathway of the brain, also known as the reward pathway, consists of two main areas that regulate dopamine (DA) and addiction-related behaviors. The ventral tegmental area (VTA) releases DA when stimulated, causing the propagation of neuronal firing along the pathway. This ends in the release of DA into the extracellular space of the nucleus accumbens (NAc), which is directly modulated by the uptake of DA. Much research has been conducted on the effects of nicotine addiction, but little research has been conducted concerning nicotine addiction and the mesolimbic pathway regarding maturation due to the small brain size. In this study, we apply our novel microstimulation experimental system to rat pups that have been perinatally exposed to nicotine. By using our self-fabricated photo-stimulation (PS) device, we can stimulate the VTA and collect dialysate, which is then used to estimate DA released into the NAc. The proposed platform has demonstrated the potential to monitor neural pathways as the pups mature. Full article

(This article belongs to the Special Issue Development of Dopaminergic Neurons 2.0)

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21 pages, 6183 KiB

Open AccessArticle

Neuronal Dot1l Activity Acts as a Mitochondrial Gene-Repressor Associated with Human Brain Aging via H3K79 Hypermethylation

by Hendrikus J. Van Heesbeen, Lars Von Oerthel, Paul M. De Vries, Cindy M. R. J. Wagemans and Marten P. Smidt

Int. J. Mol. Sci. 2023, 24(2), 1387; https://doi.org/10.3390/ijms24021387 - 10 Jan 2023

Cited by 2 | Viewed by 2147

Abstract

Methylation of histone 3 at lysine 79 (H3K79) and its catalyst, a disrupter of telomeric silencing (DOT1l), have been coupled to multiple forms of stress, such as bioenergetic and ER challenges. However, studies on H3K79 methylation and Dot1l in the (aging) brain and neurons are limited. This, together with the increasing evidence of a dynamic neuroepigenome, made us wonder if H3K79 methylation and its activator Dot1l could play important roles in brain aging and associated disorders. In aged humans, we found strong and consistent global hypermethylation of H3K79 in neurons. Specific in dopaminergic neurons, we found a strong increase in H3K79 methylation in lipofucsin positive neurons, which are linked to pathology. In animals, where we conditionally removed Dot1l, we found a rapid loss of H3K79 methylation. As a consequence, we found some decrease in specific dopaminergic genes, and surprisingly, a clear up-regulation of almost all genes belonging to the family of the respiratory chain. These data, in relation to the observed increase in global H3K79 methylation, suggest that there is an inverse relationship between H3K79 methylation and the capacity of energy metabolism in neuronal systems. Full article

(This article belongs to the Special Issue Development of Dopaminergic Neurons 2.0)

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29 pages, 4275 KiB

Open AccessArticle

Axonal Tract Reconstruction Using a Tissue-Engineered Nigrostriatal Pathway in a Rat Model of Parkinson’s Disease

by Laura A. Struzyna, Kevin D. Browne, Justin C. Burrell, Wisberty J. Gordián Vélez, Kathryn L. Wofford, Hilton M. Kaplan, N. Sanjeeva Murthy, H. Isaac Chen, John E. Duda, Rodrigo A. España and D. Kacy Cullen

Int. J. Mol. Sci. 2022, 23(22), 13985; https://doi.org/10.3390/ijms232213985 - 12 Nov 2022

Cited by 8 | Viewed by 2443

Abstract

Parkinson’s disease (PD) affects 1–2% of people over 65, causing significant morbidity across a progressive disease course. The classic PD motor deficits are caused by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), resulting in the loss of their long-distance axonal projections that modulate striatal output. While contemporary treatments temporarily alleviate symptoms of this disconnection, there is no approach able to replace the nigrostriatal pathway. We applied microtissue engineering techniques to create a living, implantable tissue-engineered nigrostriatal pathway (TE-NSP) that mimics the architecture and function of the native pathway. TE-NSPs comprise a discrete population of dopaminergic neurons extending long, bundled axonal tracts within the lumen of hydrogel micro-columns. Neurons were isolated from the ventral mesencephalon of transgenic rats selectively expressing the green fluorescent protein in dopaminergic neurons with subsequent fluorescent-activated cell sorting to enrich a population to 60% purity. The lumen extracellular matrix and growth factors were varied to optimize cytoarchitecture and neurite length, while immunocytochemistry and fast-scan cyclic voltammetry (FSCV) revealed that TE-NSP axons released dopamine and integrated with striatal neurons in vitro. Finally, TE-NSPs were implanted to span the nigrostriatal pathway in a rat PD model with a unilateral 6-hydroxydopamine SNpc lesion. Immunohistochemistry and FSCV established that transplanted TE-NSPs survived, maintained their axonal tract projections, extended dopaminergic neurites into host tissue, and released dopamine in the striatum. This work showed proof of concept that TE-NSPs can reconstruct the nigrostriatal pathway, providing motivation for future studies evaluating potential functional benefits and long-term durability of this strategy. This pathway reconstruction strategy may ultimately replace lost neuroarchitecture and alleviate the cause of motor symptoms for PD patients. Full article

(This article belongs to the Special Issue Development of Dopaminergic Neurons 2.0)

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14 pages, 2150 KiB

Open AccessArticle

The Influence of Prenatal Exposure to Quetiapine Fumarate on the Development of Dopaminergic Neurons in the Ventral Midbrain of Mouse Embryos

by Walaa F. Alsanie, Sherin Abdelrahman, Majid Alhomrani, Ahmed Gaber, Ebtisam Abdulah Alosimi, Hamza Habeeballah, Heba A. Alkhatabi, Raed I. Felimban, Charlotte A. E. Hauser, Hossam H. Tayeb, Abdulhakeem S. Alamri, Abdulwahab Alamri, Bassem M. Raafat, Khaled A. Alswat, Yusuf S. Althobaiti and Yousif A. Asiri

Int. J. Mol. Sci. 2022, 23(20), 12352; https://doi.org/10.3390/ijms232012352 - 15 Oct 2022

Cited by 2 | Viewed by 2389

Abstract

The effects of second-generation antipsychotics on prenatal neurodevelopment, apoptotic neurodegeneration, and postnatal developmental delays have been poorly investigated. Even at standard doses, the use of quetiapine fumarate (QEPF) in pregnant women might be detrimental to fetal development. We used primary mouse embryonic neurons to evaluate the disruption of morphogenesis and differentiation of ventral midbrain (VM) neurons after exposure to QEPF. The dopaminergic VM neurons were deliberately targeted due to their roles in cognition, motor activity, and behavior. The results revealed that exposure to QEPF during early brain development decreased the effects of the dopaminergic lineage-related genes Tyrosine hydroxylase(Th), Dopamine receptor D1 (Drd1), Dopamine transporter (Dat), LIM homeobox transcription factor 1 alfa (Lmx1a), and Cell adhesion molecule L1 (Chl1), and the senescent dopaminergic gene Pituitary homeobox 3 (Pitx3). In contrast, Brain derived neurotrophic factor (Bdnf) and Nuclear receptor-related 1 (Nurr1) expressions were significantly upregulated. Interestingly, QEPF had variable effects on the development of non-dopaminergic neurons in VM. An optimal dose of QEPF (10 µM) was found to insignificantly affect the viability of neurons isolated from the VM. It also instigated a non-significant reduction in adenosine triphosphate formation in these neuronal populations. Exposure to QEPF during the early stages of brain development could also hinder the formation of VM and their structural phenotypes. These findings could aid therapeutic decision-making when prescribing 2nd generation antipsychotics in pregnant populations. Full article

(This article belongs to the Special Issue Development of Dopaminergic Neurons 2.0)

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Review

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16 pages, 868 KiB

Open AccessReview

The Crucial Roles of Pitx3 in Midbrain Dopaminergic Neuron Development and Parkinson’s Disease-Associated Neurodegeneration

by Xin Wang, Xi Chen, Guangdong Liu, Huaibin Cai and Weidong Le

Int. J. Mol. Sci. 2023, 24(10), 8614; https://doi.org/10.3390/ijms24108614 - 11 May 2023

Cited by 4 | Viewed by 2454

Abstract

The degeneration of midbrain dopaminergic (mDA) neurons, particularly in the substantia nigra pars compacta (SNc), is one of the most prominent pathological hallmarks of Parkinson’s disease (PD). To uncover the pathogenic mechanisms of mDA neuronal death during PD may provide therapeutic targets to prevent mDA neuronal loss and slow down the disease’s progression. Paired-like homeodomain transcription factor 3 (Pitx3) is selectively expressed in the mDA neurons as early as embryonic day 11.5 and plays a critical role in mDA neuron terminal differentiation and subset specification. Moreover, Pitx3-deficient mice exhibit some canonical PD-related features, including the profound loss of SNc mDA neurons, a dramatic decrease in striatal dopamine (DA) levels, and motor abnormalities. However, the precise role of Pitx3 in progressive PD and how this gene contributes to mDA neuronal specification during early stages remains unclear. In this review, we updated the latest findings on Pitx3 by summarizing the crosstalk between Pitx3 and its associated transcription factors in mDA neuron development. We further explored the potential benefits of Pitx3 as a therapeutic target for PD in the future. To better understand the transcriptional network of Pitx3 in mDA neuron development may provide insights into Pitx3-related clinical drug-targeting research and therapeutic approaches. Full article

(This article belongs to the Special Issue Development of Dopaminergic Neurons 2.0)

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18 pages, 1924 KiB

Open AccessReview

Gut-to-Brain α-Synuclein Transmission in Parkinson’s Disease: Evidence for Prion-like Mechanisms

by Merry Chen and Danielle E. Mor

Int. J. Mol. Sci. 2023, 24(8), 7205; https://doi.org/10.3390/ijms24087205 - 13 Apr 2023

Cited by 17 | Viewed by 4027

Abstract

Parkinson’s disease (PD) is a multifactorial disorder involving both motor and non-motor symptoms caused by the progressive death of distinct neuronal populations, including dopaminergic neurons in the substantia nigra. The deposition of aggregated α-synuclein protein into Lewy body inclusions is a hallmark of the disorder, and α-synuclein pathology has been found in the enteric nervous system (ENS) of PD patients up to two decades prior to diagnosis. In combination with the high occurrence of gastrointestinal dysfunction in early stages of PD, current evidence strongly suggests that some forms of PD may originate in the gut. In this review, we discuss human studies that support ENS Lewy pathology as a characteristic feature of PD, and present evidence from humans and animal model systems that α-synuclein aggregation may follow a prion-like spreading cascade from enteric neurons, through the vagal nerve, and into the brain. Given the accessibility of the human gut to pharmacologic and dietary interventions, therapeutic strategies aimed at reducing pathological α-synuclein in the gastrointestinal tract hold significant promise for PD treatment. Full article

(This article belongs to the Special Issue Development of Dopaminergic Neurons 2.0)

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26 pages, 992 KiB

Open AccessReview

From 2D to 3D: Development of Monolayer Dopaminergic Neuronal and Midbrain Organoid Cultures for Parkinson’s Disease Modeling and Regenerative Therapy

by Yee Jie Yeap, Tng J. W. Teddy, Mok Jung Lee, Micaela Goh and Kah Leong Lim

Int. J. Mol. Sci. 2023, 24(3), 2523; https://doi.org/10.3390/ijms24032523 - 28 Jan 2023

Cited by 8 | Viewed by 3844

Abstract

Parkinson’s Disease (PD) is a prevalent neurodegenerative disorder that is characterized pathologically by the loss of A9-specific dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) of the midbrain. Despite intensive research, the etiology of PD is currently unresolved, and the disease remains incurable. This, in part, is due to the lack of an experimental disease model that could faithfully recapitulate the features of human PD. However, the recent advent of induced pluripotent stem cell (iPSC) technology has allowed PD models to be created from patient-derived cells. Indeed, DA neurons from PD patients are now routinely established in many laboratories as monolayers as well as 3D organoid cultures that serve as useful toolboxes for understanding the mechanism underlying PD and also for drug discovery. At the same time, the iPSC technology also provides unprecedented opportunity for autologous cell-based therapy for the PD patient to be performed using the patient’s own cells as starting materials. In this review, we provide an update on the molecular processes underpinning the development and differentiation of human pluripotent stem cells (PSCs) into midbrain DA neurons in both 2D and 3D cultures, as well as the latest advancements in using these cells for drug discovery and regenerative medicine. For the novice entering the field, the cornucopia of differentiation protocols reported for the generation of midbrain DA neurons may seem daunting. Here, we have distilled the essence of the different approaches and summarized the main factors driving DA neuronal differentiation, with the view to provide a useful guide to newcomers who are interested in developing iPSC-based models of PD. Full article

(This article belongs to the Special Issue Development of Dopaminergic Neurons 2.0)

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