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Animal Models of Parkinson's Disease and Related Disorders

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Guest Editor
Department of Research for Parkinson's Disease, Juntendo University Graduate School of Medicine, Tokyo, Japan
Interests: Drosophila genetics; neurodegeneration; Parkinson's disease; iPS cells; mitochondria; synaptic dynamics; unfolded protein stress
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Special Issue Information

Dear colleagues,

Parkinson's disease (PD), one of the most common movement disorders, is characterized by age-dependent dysfunction and degeneration of the midbrain dopaminergic neurons. Understanding of the pathogenic mechanisms of PD has progressed with neurotoxin-induced and α-synunclein propagation models. Moreover, recent advances in human molecular genetics have led to the identification of familial and PD risk genes. Analyses of model animals in which mutations of these PD genes are introduced promise to shed light on the pathogenic mechanisms underlying both idiopathic and familial PD.

We invite authors to submit manuscripts focused on the molecular mechanisms of neurodegeneration, therapeutic challenges using model animals, the development of new screening methods, and the generation of new PD and related models to this Special Issue. Both high-quality research articles and reviews of the most recent progress in the area are welcome. Moreover, papers dealing with new methods to detect the degeneration of dopaminergic neurons as well as other cells are of great interest. The key topics include, but are not limited to, the following:

  • PD studies using vertebrate models;
  • PD studies using non-vertebrate models;
  • PD studies using other organisms;
  • Drug screening using PD model organisms;
  • Development of therapeutic strategies using PD model organisms;
  • Development of experimental techniques.

Prof. Yuzuru Imai
Guest Editor

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Keywords

  • α-synuclein propagation
  • mitochondrial quality control
  • mitochondrial respiratory function
  • autophagy and mitophagy
  • lysosomal functions
  • vesicular transport
  • synaptic vesicle endocytosis and recycling
  • oxidative stress and ER stress
  • lipid metabolism
  • glymphatic system
  • neuroinflammation

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Related Special Issue

Published Papers (12 papers)

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Editorial

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4 pages, 595 KiB  
Editorial
Editorial for the Special Issue “Animal Models of Parkinson’s Disease and Related Disorders”
by Yuzuru Imai
Int. J. Mol. Sci. 2020, 21(12), 4250; https://doi.org/10.3390/ijms21124250 - 15 Jun 2020
Viewed by 1986
Abstract
Parkinson’s disease (PD) is the second most common neurodegenerative disorder characterized by age-dependent motor dysfunction and degeneration of the midbrain dopaminergic neurons [...] Full article
(This article belongs to the Special Issue Animal Models of Parkinson's Disease and Related Disorders)
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Research

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20 pages, 2334 KiB  
Article
Impact of Aging on the 6-OHDA-Induced Rat Model of Parkinson’s Disease
by Sandra Barata-Antunes, Fábio G. Teixeira, Bárbara Mendes-Pinheiro, Ana V. Domingues, Helena Vilaça-Faria, Ana Marote, Deolinda Silva, Rui A. Sousa and António J. Salgado
Int. J. Mol. Sci. 2020, 21(10), 3459; https://doi.org/10.3390/ijms21103459 - 14 May 2020
Cited by 30 | Viewed by 7238
Abstract
Parkinson’s disease (PD) is the second most common age-related neurodegenerative disorder. The neurodegeneration leading to incapacitating motor abnormalities mainly occurs in the nigrostriatal pathway due to the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Several animal models have been [...] Read more.
Parkinson’s disease (PD) is the second most common age-related neurodegenerative disorder. The neurodegeneration leading to incapacitating motor abnormalities mainly occurs in the nigrostriatal pathway due to the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Several animal models have been developed not only to better understand the mechanisms underlying neurodegeneration but also to test the potential of emerging disease-modifying therapies. However, despite aging being the main risk factor for developing idiopathic PD, most of the studies do not use aged animals. Therefore, this study aimed at assessing the effect of aging in the unilateral 6-hydroxydopamine (6-OHDA)-induced animal model of PD. For this, female young adult and aged rats received a unilateral injection of 6-OHDA into the medial forebrain bundle. Subsequently, the impact of aging on 6-OHDA-induced effects on animal welfare, motor performance, and nigrostriatal integrity were assessed. The results showed that aging had a negative impact on animal welfare after surgery. Furthermore, 6-OHDA-induced impairments on skilled motor function were significantly higher in aged rats when compared with their younger counterparts. Nigrostriatal histological analysis further revealed an increased 6-OHDA-induced dopaminergic cell loss in the SNpc of aged animals when compared to young animals. Overall, our results demonstrate a higher susceptibility of aged animals to 6-OHDA toxic insult. Full article
(This article belongs to the Special Issue Animal Models of Parkinson's Disease and Related Disorders)
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18 pages, 12362 KiB  
Article
Chronic Systemic Exposure to Low-Dose Rotenone Induced Central and Peripheral Neuropathology and Motor Deficits in Mice: Reproducible Animal Model of Parkinson’s Disease
by Ikuko Miyazaki, Nami Isooka, Fuminori Imafuku, Jin Sun, Ryo Kikuoka, Chieko Furukawa and Masato Asanuma
Int. J. Mol. Sci. 2020, 21(9), 3254; https://doi.org/10.3390/ijms21093254 - 4 May 2020
Cited by 65 | Viewed by 7020
Abstract
Epidemiological studies demonstrated that pesticide exposure, such as rotenone and paraquat, increases the risk of Parkinson’s disease (PD). Chronic systemic exposure to rotenone, a mitochondrial complex I inhibitor, could reproduce many features of PD. However, the adoption of the models is limiting because [...] Read more.
Epidemiological studies demonstrated that pesticide exposure, such as rotenone and paraquat, increases the risk of Parkinson’s disease (PD). Chronic systemic exposure to rotenone, a mitochondrial complex I inhibitor, could reproduce many features of PD. However, the adoption of the models is limiting because of variability in animal sensitivity and the inability of other investigators to consistently reproduce the PD neuropathology. In addition, most of rotenone models were produced in rats. Here, we tried to establish a high-reproducible rotenone model using C57BL/6J mice. The rotenone mouse model was produced by chronic systemic exposure to a low dose of rotenone (2.5 mg/kg/day) for 4 weeks by subcutaneous implantation of rotenone-filled osmotic mini pump. The rotenone-treated mice exhibited motor deficits assessed by open field, rotarod and cylinder test and gastrointestinal dysfunction. Rotenone treatment decreased the number of dopaminergic neuronal cells in the substantia nigra pars compacta (SNpc) and lesioned nerve terminal in the striatum. In addition, we observed significant reduction of cholinergic neurons in the dorsal motor nucleus of the vagus (DMV) and the intestinal myenteric plexus. Moreover, α-synuclein was accumulated in neuronal soma in the SNpc, DMV and intestinal myenteric plexus in rotenone-treated mice. These data suggest that the low-dose rotenone mouse model could reproduce behavioral and central and peripheral neurodegenerative features of PD and be a useful model for investigation of PD pathogenesis. Full article
(This article belongs to the Special Issue Animal Models of Parkinson's Disease and Related Disorders)
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18 pages, 2107 KiB  
Article
Comparison between Tail Suspension Swing Test and Standard Rotation Test in Revealing Early Motor Behavioral Changes and Neurodegeneration in 6-OHDA Hemiparkinsonian Rats
by Ilaria Rosa, Davide Di Censo, Brigida Ranieri, Giuseppe Di Giovanni, Eugenio Scarnati, Marcello Alecci, Angelo Galante and Tiziana Marilena Florio
Int. J. Mol. Sci. 2020, 21(8), 2874; https://doi.org/10.3390/ijms21082874 - 20 Apr 2020
Cited by 13 | Viewed by 8738
Abstract
The unilateral 6-hydroxydopamine (6-OHDA) model of Parkinson’s disease (PD) is one of the most commonly used in rodents. The anatomical, metabolic, and behavioral changes that occur after severe and stable 6-OHDA lesions have been extensively studied. Here, we investigated whether early motor behavioral [...] Read more.
The unilateral 6-hydroxydopamine (6-OHDA) model of Parkinson’s disease (PD) is one of the most commonly used in rodents. The anatomical, metabolic, and behavioral changes that occur after severe and stable 6-OHDA lesions have been extensively studied. Here, we investigated whether early motor behavioral deficits can be observed in the first week after the injection of 6-OHDA into the right substantia nigra pars compacta (SNc), and if they were indicative of the severity of the dopaminergic (DAergic) lesion in the SNc and the striatum at different time-points (day 1, 3, 5, 7, 14, 21). With this aim, we used our newly modified tail suspension swing test (TSST), the standard rotation test (RT), and immunohistochemical staining for tyrosine hydroxylase (TH). The TSST, but not the standard RT, revealed a spontaneous motor bias for the 6-OHDA-lesioned rats from the day 1 post-surgery. Both tests detected the motor asymmetry induced by (single and repeated) apomorphine (APO) challenges that correlated, in the first week, with the DAergic neuronal degeneration. The described TSST is fast and easy to perform, and in the drug-free condition is useful for the functional assessment of early motor asymmetry appearing after the 6-OHDA-lesion in the SNc, without the confounding effect of APO challenges. Full article
(This article belongs to the Special Issue Animal Models of Parkinson's Disease and Related Disorders)
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15 pages, 2808 KiB  
Article
PERK-Mediated eIF2α Phosphorylation Contributes to The Protection of Dopaminergic Neurons from Chronic Heat Stress in Drosophila
by Rosalie Elvira, Sun Joo Cha, Gyeong-Mu Noh, Kiyoung Kim and Jaeseok Han
Int. J. Mol. Sci. 2020, 21(3), 845; https://doi.org/10.3390/ijms21030845 - 28 Jan 2020
Cited by 21 | Viewed by 4807
Abstract
Environmental high-temperature heat exposure is linked to physiological stress such as disturbed protein homeostasis caused by endoplasmic reticulum (ER) stress. Abnormal proteostasis in neuronal cells is a common pathological factor of Parkinson’s disease (PD). Chronic heat stress is thought to induce neuronal cell [...] Read more.
Environmental high-temperature heat exposure is linked to physiological stress such as disturbed protein homeostasis caused by endoplasmic reticulum (ER) stress. Abnormal proteostasis in neuronal cells is a common pathological factor of Parkinson’s disease (PD). Chronic heat stress is thought to induce neuronal cell death during the onset and progression of PD, but the exact role and mechanism of ER stress and the activation of the unfolded protein response (UPR) remains unclear. Here, we showed that chronic heat exposure induces ER stress mediated by the PKR-like eukaryotic initiation factor 2α kinase (PERK)/eIF2α phosphorylation signaling pathway in Drosophila neurons. Chronic heat-induced eIF2α phosphorylation was regulated by PERK activation and required for neuroprotection from chronic heat stress. Moreover, the attenuated protein synthesis by eIF2α phosphorylation was a critical factor for neuronal cell survival during chronic heat stress. We further showed that genetic downregulation of PERK, specifically in dopaminergic (DA) neurons, impaired motor activity and led to DA neuron loss. Therefore, our findings provide in vivo evidence demonstrating that chronic heat exposure may be a critical risk factor in the onset of PD, and eIF2α phosphorylation mediated by PERK may contribute to the protection of DA neurons against chronic heat stress in Drosophila. Full article
(This article belongs to the Special Issue Animal Models of Parkinson's Disease and Related Disorders)
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14 pages, 2838 KiB  
Article
Serotonin 5-HT4 Receptor Agonists Improve Facilitation of Contextual Fear Extinction in an MPTP-Induced Mouse Model of Parkinson’s Disease
by Toshiaki Ishii, Ken-ichi Kinoshita and Yoshikage Muroi
Int. J. Mol. Sci. 2019, 20(21), 5340; https://doi.org/10.3390/ijms20215340 - 26 Oct 2019
Cited by 19 | Viewed by 3775
Abstract
Previously, we found that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson’s disease (PD) model mice (PD mice) showed facilitation of hippocampal memory extinction via reduced cyclic adenosine monophosphate (cAMP)/cAMP-dependent response element-binding protein (CREB) signaling, which may cause cognitive impairment in PD. Serotonergic neurons in the median raphe [...] Read more.
Previously, we found that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson’s disease (PD) model mice (PD mice) showed facilitation of hippocampal memory extinction via reduced cyclic adenosine monophosphate (cAMP)/cAMP-dependent response element-binding protein (CREB) signaling, which may cause cognitive impairment in PD. Serotonergic neurons in the median raphe nucleus (MnRN) project to the hippocampus, and functional abnormalities have been reported. In the present study, we investigated the effects of the serotonin 5-HT4 receptor (5-HT4R) agonists prucalopride and velusetrag on the facilitation of memory extinction observed in PD mice. Both 5-HT4R agonists restored facilitation of contextual fear extinction in PD mice by stimulating the cAMP/CREB pathway in the dentate gyrus of the hippocampus. A retrograde fluorogold-tracer study showed that γ-aminobutyric acid-ergic (GABAergic) neurons in the reticular part of the substantia nigra (SNr), but not dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc), projected to serotonergic neurons in the MnRN, which are known to project their nerve terminals to the hippocampus. It is possible that the degeneration of the SNpc DAergic neurons in PD mice affects the SNr GABAergic neurons, and thereafter, the serotonergic neurons in the MnRN, resulting in hippocampal dysfunction. These findings suggest that 5HT4R agonists could be potentially useful as therapeutic drugs for treating cognitive deficits in PD. Full article
(This article belongs to the Special Issue Animal Models of Parkinson's Disease and Related Disorders)
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Review

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19 pages, 1390 KiB  
Review
Lipids: Key Players That Modulate α-Synuclein Toxicity and Neurodegeneration in Parkinson’s Disease
by Akio Mori, Yuzuru Imai and Nobutaka Hattori
Int. J. Mol. Sci. 2020, 21(9), 3301; https://doi.org/10.3390/ijms21093301 - 7 May 2020
Cited by 35 | Viewed by 6244
Abstract
Parkinson’s disease (PD) is the second most common neurodegenerative disease; it is characterized by the loss of dopaminergic neurons in the midbrain and the accumulation of neuronal inclusions, mainly consisting of α-synuclein (α-syn) fibrils in the affected regions. The prion-like property of the [...] Read more.
Parkinson’s disease (PD) is the second most common neurodegenerative disease; it is characterized by the loss of dopaminergic neurons in the midbrain and the accumulation of neuronal inclusions, mainly consisting of α-synuclein (α-syn) fibrils in the affected regions. The prion-like property of the pathological forms of α-syn transmitted via neuronal circuits has been considered inherent in the nature of PD. Thus, one of the potential targets in terms of PD prevention is the suppression of α-syn conversion from the functional form to pathological forms. Recent studies suggested that α-syn interacts with synaptic vesicle membranes and modulate the synaptic functions. A series of studies suggest that transient interaction of α-syn as multimers with synaptic vesicle membranes composed of phospholipids and other lipids is required for its physiological function, while an α-syn-lipid interaction imbalance is believed to cause α-syn aggregation and the resultant pathological α-syn conversion. Altered lipid metabolisms have also been implicated in the modulation of PD pathogenesis. This review focuses on the current literature reporting the role of lipids, especially phospholipids, and lipid metabolism in α-syn dynamics and aggregation processes. Full article
(This article belongs to the Special Issue Animal Models of Parkinson's Disease and Related Disorders)
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13 pages, 2032 KiB  
Review
Possible Role of Amyloidogenic Evolvability in Dementia with Lewy Bodies: Insights from Transgenic Mice Expressing P123H β-Synuclein
by Masayo Fujita, Gilbert Ho, Yoshiki Takamatsu, Ryoko Wada, Kazutaka Ikeda and Makoto Hashimoto
Int. J. Mol. Sci. 2020, 21(8), 2849; https://doi.org/10.3390/ijms21082849 - 19 Apr 2020
Cited by 3 | Viewed by 2781
Abstract
Dementia with Lewy bodies (DLB) is the second most prevalent neurodegenerative dementia after Alzheimer’s disease, and is pathologically characterized by formation of intracellular inclusions called Lewy bodies, the major constituent of which is aggregated α-synuclein (αS). Currently, neither a mechanistic etiology nor an [...] Read more.
Dementia with Lewy bodies (DLB) is the second most prevalent neurodegenerative dementia after Alzheimer’s disease, and is pathologically characterized by formation of intracellular inclusions called Lewy bodies, the major constituent of which is aggregated α-synuclein (αS). Currently, neither a mechanistic etiology nor an effective disease-modifying therapy for DLB has been established. Although two missense mutations of β-synuclein (βS), V70M and P123H, were identified in sporadic and familial DLB, respectively, the precise mechanisms through which βS mutations promote DLB pathogenesis remain elusive. To further clarify such mechanisms, we investigated transgenic (Tg) mice expressing P123H βS, which develop progressive neurodegeneration in the form of axonal swelling and non-motor behaviors, such as memory dysfunction and depression, which are more prominent than motor deficits. Furthermore, cross-breeding of P123H βS Tg mice with αS Tg mice worsened the neurodegenerative phenotype presumably through the pathological cross-seeding of P123H βS with αS. Collectively, we predict that βS misfolding due to gene mutations might be pathogenic. In this paper, we will discuss the possible involvement of amyloidogenic evolvability in the pathogenesis of DLB based on our previous papers regarding the P123H βS Tg mice. Given that stimulation of αS evolvability by P123H βS may underlie neuropathology in our mouse model, more radical disease-modifying therapy might be derived from the evolvability mechanism. Additionally, provided that altered βS were involved in the pathogenesis of sporadic DLB, the P123H βS Tg mice could be used for investigating the mechanism and therapy of DLB. Full article
(This article belongs to the Special Issue Animal Models of Parkinson's Disease and Related Disorders)
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14 pages, 293 KiB  
Review
Historical Perspective: Models of Parkinson’s Disease
by Shyh Jenn Chia, Eng-King Tan and Yin-Xia Chao
Int. J. Mol. Sci. 2020, 21(7), 2464; https://doi.org/10.3390/ijms21072464 - 2 Apr 2020
Cited by 219 | Viewed by 19438
Abstract
Parkinson’s disease (PD) is the most common movement disorder with motor and nonmotor signs. The current therapeutic regimen for PD is mainly symptomatic as the etio-pathophysiology has not been fully elucidated. A variety of animal models has been generated to study different aspects [...] Read more.
Parkinson’s disease (PD) is the most common movement disorder with motor and nonmotor signs. The current therapeutic regimen for PD is mainly symptomatic as the etio-pathophysiology has not been fully elucidated. A variety of animal models has been generated to study different aspects of the disease for understanding the pathogenesis and therapeutic development. The disease model can be generated through neurotoxin-based or genetic-based approaches in a wide range of animals such as non-human primates (NHP), rodents, zebrafish, Caenorhabditis (C.) elegans, and drosophila. Cellular-based disease model is frequently used because of the ease of manipulation and suitability for large-screen assays. In neurotoxin-induced models, chemicals such as 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, and paraquat are used to recapitulate the disease. Genetic manipulation of PD-related genes, such as α-Synuclein(SNCA), Leucine-rich repeat kinase 2 (LRRK2), Pten-Induced Kinase 1 (PINK1), Parkin(PRKN), and Protein deglycase (DJ-1) Are used in the transgenic models. An emerging model that combines both genetic- and neurotoxin-based methods has been generated to study the role of the immune system in the pathogenesis of PD. Here, we discuss the advantages and limitations of the different PD models and their utility for different research purposes. Full article
(This article belongs to the Special Issue Animal Models of Parkinson's Disease and Related Disorders)
12 pages, 547 KiB  
Review
Animal Model for Prodromal Parkinson’s Disease
by Tomoyuki Taguchi, Masashi Ikuno, Hodaka Yamakado and Ryosuke Takahashi
Int. J. Mol. Sci. 2020, 21(6), 1961; https://doi.org/10.3390/ijms21061961 - 13 Mar 2020
Cited by 36 | Viewed by 9718
Abstract
Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra and subsequent motor symptoms, but various non-motor symptoms (NMS) often precede motor symptoms. Recently, NMS have attracted much attention as a clue for identifying patients in a prodromal [...] Read more.
Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra and subsequent motor symptoms, but various non-motor symptoms (NMS) often precede motor symptoms. Recently, NMS have attracted much attention as a clue for identifying patients in a prodromal stage of PD, which is an excellent point at which to administer disease-modifying therapies (DMTs). These prodromal symptoms include olfactory loss, constipation, and sleep disorders, especially rapid eye movement sleep behavior disorder (RBD), all of which are also important for elucidating the mechanisms of the initiation and progression of the disease. For the development of DMTs, an animal model that reproduces the prodromal stage of PD is also needed. There have been various mammalian models reported, including toxin-based, genetic, and alpha synuclein propagation models. In this article, we review the animal models that exhibit NMS as prodromal symptoms and also discuss an appropriate prodromal model and its importance for the development of DMT of PD. Full article
(This article belongs to the Special Issue Animal Models of Parkinson's Disease and Related Disorders)
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14 pages, 1471 KiB  
Review
Mitochondrial E3 Ubiquitin Ligase Parkin: Relationships with Other Causal Proteins in Familial Parkinson’s Disease and Its Substrate-Involved Mouse Experimental Models
by Satoru Torii, Shuya Kasai, Tatsushi Yoshida, Ken-ichi Yasumoto and Shigeomi Shimizu
Int. J. Mol. Sci. 2020, 21(4), 1202; https://doi.org/10.3390/ijms21041202 - 11 Feb 2020
Cited by 7 | Viewed by 4526
Abstract
Parkinson’s disease (PD) is a common neurodegenerative disorder. Recent identification of genes linked to familial forms of PD has revealed that post-translational modifications, such as phosphorylation and ubiquitination of proteins, are key factors in disease pathogenesis. In PD, E3 ubiquitin ligase Parkin and [...] Read more.
Parkinson’s disease (PD) is a common neurodegenerative disorder. Recent identification of genes linked to familial forms of PD has revealed that post-translational modifications, such as phosphorylation and ubiquitination of proteins, are key factors in disease pathogenesis. In PD, E3 ubiquitin ligase Parkin and the serine/threonine-protein kinase PTEN-induced kinase 1 (PINK1) mediate the mitophagy pathway for mitochondrial quality control via phosphorylation and ubiquitination of their substrates. In this review, we first focus on well-characterized PINK1 phosphorylation motifs. Second, we describe our findings concerning relationships between Parkin and HtrA2/Omi, a protein involved in familial PD. Third, we describe our findings regarding inhibitory PAS (Per/Arnt/Sim) domain protein (IPAS), a member of PINK1 and Parkin substrates, involved in neurodegeneration during PD. IPAS is a dual-function protein involved in transcriptional repression of hypoxic responses and the pro-apoptotic activities. Full article
(This article belongs to the Special Issue Animal Models of Parkinson's Disease and Related Disorders)
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16 pages, 241 KiB  
Review
Selecting an Appropriate Animal Model of Depression
by Yuanzhen Hao, Huixiang Ge, Mengyun Sun and Yun Gao
Int. J. Mol. Sci. 2019, 20(19), 4827; https://doi.org/10.3390/ijms20194827 - 28 Sep 2019
Cited by 155 | Viewed by 20894
Abstract
Depression has become one of the most severe psychiatric disorders and endangers the health of living beings all over the world. In order to explore the molecular mechanism that underlies depression, different kinds of animal models of depression are used in laboratory experiments. [...] Read more.
Depression has become one of the most severe psychiatric disorders and endangers the health of living beings all over the world. In order to explore the molecular mechanism that underlies depression, different kinds of animal models of depression are used in laboratory experiments. However, a credible and reasonable animal model that is capable of imitating the pathologic mechanism of depression in mankind has yet to be found, resulting in a barrier to further investigation of depression. Nevertheless, it is possible to explain the pathologic mechanism of depression to a great extent by a rational modeling method and behavioral testing. This review aims to provide a reference for researchers by comparing the advantages and disadvantages of some common animal depression models. Full article
(This article belongs to the Special Issue Animal Models of Parkinson's Disease and Related Disorders)
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