Submitted Successfully!
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Ver. Summary Created by Modification Content Size Created at Operation
1 + 2601 word(s) 2601 2021-10-14 05:51:24 |
2 format correction Meta information modification 2601 2021-10-22 08:25:06 |

Video Upload Options

Do you have a full video?


Are you sure to Delete?
If you have any further questions, please contact Encyclopedia Editorial Office.
Cao, H. Animal Models for Human Neurodegenerative Diseases. Encyclopedia. Available online: (accessed on 08 December 2023).
Cao H. Animal Models for Human Neurodegenerative Diseases. Encyclopedia. Available at: Accessed December 08, 2023.
Cao, Hong. "Animal Models for Human Neurodegenerative Diseases" Encyclopedia, (accessed December 08, 2023).
Cao, H.(2021, October 22). Animal Models for Human Neurodegenerative Diseases. In Encyclopedia.
Cao, Hong. "Animal Models for Human Neurodegenerative Diseases." Encyclopedia. Web. 22 October, 2021.
Animal Models for Human Neurodegenerative Diseases

Animal models of human neurodegenerative disease have been investigated for several decades. In recent years, zebrafish (Danio rerio) and medaka (Oryzias latipes) have become popular in pathogenic and therapeutic studies about human neurodegenerative diseases due to their small size, the optical clarity of embryos, their fast development, and their suitability to large-scale therapeutic screening. 

zebrafish medaka disease models neurodegenerative

1. Introduction

Neurodegenerative diseases are a major threat to human health. With the increase in the elderly population, these age-dependent diseases are becoming increasingly prevalent [1]. These disorders are devastating to families, and they represent a huge burden for society. Hence, it is urgent to develop novel and more effective therapeutic strategies to remedy these diseases. Animal models were confirmed as a useful tool to investigate the complex mechanisms of neurodegenerative diseases.
Over the past several decades, animal models, such as mice, monkeys, dogs, pigs, fruit flies, and fish, have contributed greatly to our understanding of the genetic basis of the cellular and molecular mechanisms behind neurodegenerative diseases [2][3][4][5][6]. In particular, small fish such as zebrafish (Danio rerio) and medaka (Oryzias latipes) offer several advantages as model organisms for human neurodegenerative disease studies and drug discovery. Due to their relatively small size and short lifespan, they require less space and are more cost-efficient for laboratory maintenance compared with other vertebrate model organisms, such as the mouse. In addition, they have very high fecundity, and their embryos are transparent during development, which facilitates the non-invasive visualization of its development, and complex mechanisms of neurodegeneration can be analysed more rapidly than in mouse and other vertebrate animal models [7][8][9][10][11].
Finally, drugs can be administered by intraperitoneal injection or oral gavage in adult zebrafish [12] or medaka [13], whereas in larvae or embryos, they are always administered by adding them to the water and drug solution [14]. Due to their small size, they can be easily treated in the 24-well plate, 96-well plate, or 10-cm Petri dish. This facilitates subsequent analysis of phenotypes after drug treatment. Therefore, all these characteristics make them suitable for large-scale and high-throughput drug screening scans.
On the other hand, the identity of nucleotide or amino acid sequences between zebrafish and human homologues is approximately 71% [15], which is much higher than some invertebrate animal models such as roundworms (Caenorhabditis elegans) (30–60%) [16] and fruit flies (Drosophila melanogaster) (40%) [17]. Notably, zebrafish possess a vertebrate neural structural organisation, and all of the major structures are similar to the mammalian brain. Furthermore, zebrafish also possesses a functional Blood–Brain Barrier (BBB), similar to humans [18]. Many important neurotransmitters were detected in the neurotransmitter profile of zebrafish, which is very important for neuroscientific studies [19].
Although the zebrafish is the most widely used fish model globally, medaka is also used extensively, especially in Europe and Asia [20]. Compared with the zebrafish, the embryos of medaka tolerate a wider temperature range (4–35 °C until the onset of heartbeat and 18–35 °C thereafter, compared to 25–33 °C in zebrafish) [11][21]. This provides great convenience in screens for isolation of low temperature-sensitive gene mutations and the manipulation of developmental rates [11]. In addition, medaka has a long history as a genetic model system. Therefore, a lot of inbred strains from different populations with a high degree of genetic polymorphism are available. This facilitates the generation of high-resolution genetic maps and the genetic analysis of monogenic traits and quantitative trait loci [21].
Therefore, all these factors make zebrafish and medaka of great value in studies of neurodegenerative diseases [22]. As a result, the publications in PubMed using zebrafish, the more popular model of the two, as the neurodegenerative disease model increased sharply in recent years (Figure 1).
Figure 1. Absolute number of articles for zebrafish neurodegenerative diseases modelper year of publication extracted from the PubMed database.

2. Parkinson’s Disease Models

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases that affects the motor system. Surveys, medical records, and death certificates demonstrate that the prevalence of PD has notably increased worldwide in recent years, possibly due to the growing elderly population worldwide [23][24][25]. The prevalence of PD was approximately 8.52 million and the incidence was 1.02 million in 2017 globally [26], whereas approximately 0.34 million people died from PD in 2017 globally [27]. It is predicted that the number of cases will reach 12 million by 2050 [28]. In spite of extensive studies that focus on the epidemiology and possible treatments of PD, its pathogenic mechanism has not been fully elucidated, and there is still no effective therapeutic strategy to cure this disease [29]. Compared with some traditional mammal models such as mice, zebrafish and medaka have comparative advantages for the pathological research of PD due to their short life cycles and high fecundity, which makes them particularly suitable for large scale drug screening [14][30][31][32]. In addition, as vertebrate species, zebrafish and medaka have higher genetic similarity to humans than invertebrate model animals such as roundworms and fruit flies [15][16][17][20]. In this review, we summarize several studies of PD in zebrafish, focusing on those published in recent years (Table 1) and several studies of PD in medaka. We discuss two main types of models: neurotoxin-induced and genetic models.
Table 1. Zebrafish models of Parkinson’s disease.







Motor impairments and weakened touch sensory

Reduction of locomotor activity and dopaminergic neuron, over-expression of synuclein in the optic tectum




Motor impairments and anxiety

Reduction of dopaminergic neurons and morphological alternations




Motor impairments, various developmental anomalies

The paraquat-treated zebrafish did not recapitulate PD pathology




Motor impairments, anxiety, and olfactory dysfunction

In addition to motor impairments, they also show Olfactory dysfunction, which is a typical non-motor symptom of PD




No abnormalities in swimming behavior

Loss of the DA neuron numbers in the diencephalon, whereas no abnormalities in swimming behavior





Motor impairment and oxidative stress

Reduction of dopaminergic neurons, dis-organized diencephalic dopaminergic neurons, and the pink1 gene are sensitive markers of oxidative stress in zebrafish




Motor impairment

Loss of neuronal cells and synuclein aggregation, similar to the phenotype of PD in humans





Motor impairment

With aging, exhibit lower TH levels, respiratory failure in skeletal muscle, and lower body mass, particularly in the male fish




Motor impairment

Led to cell death in larval zebrafish sensory neurons




Motor impairment

Reduction of the GBA protein, dopaminergic, and noradrenergic neurons





Motor impairment and olfactory dysfunction

Reduced DA neuronal population and dysregulation of the PINK1/Parkin mitophagy pathway


3. Alzheimer’s Disease Models

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive memory loss, cognitive impairment, behavioural changes, and loss of functional abilities [66][67][68][69]. AD is the most prevalent form of dementia. It is estimated that nowadays more than 50 million people worldwide have dementia, and this number is expected to reach over 150 million by the 2050 [67]. AD is irreversible and it causes about 70% of all dementia cases [68]. Unfortunately, it still cannot be prevented, treated, or cured. The drug discovery for AD is very challenging, so no new drugs have been approved since 2003, when Memantine was approved [66][67][68][70]. Including four drugs that are approved by the Food and Drug Administration (FDA), at present there are only five approved drugs on the market available for the treatment of AD [68][71]. In addition, a previous study demonstrated that oxidative stress may induce behavioural and cognitive impairments in the aging zebrafish, just as it does in mammals [72]. Below, we describe previous studies of the molecular mechanisms of AD in zebrafish (Table 2).
Table 2. Zebrafish models of Alzheimer’s disease.







Intracellular depositions

Link between aging, neurogenesis, regenerative, neuroinflammation, and neural stem cell plasticity


Okadaic acid


Cognitive and memory impairments, neuroinflammation cholinergic dysfunction, glutamate excitotoxicity, and mitochondrial dysfunction

Provide all the major molecular hallmarks of AD


Cigarette smoke extract


Neurocognitive dysfunction

Enhancement of the acetylcholinesterase activity


Aluminum chloride


Neurocognitive dysfunction, memory impairment

Impaired locomotor activity, learning, and memory abilities




Memory impairment

Reduction of the glutathione S-transferase (GST) activity in the gill




Cognition and exploratory behavior

Impairment of aversive long-term memory and distance traveled movement time




Motor impairment

The phenotypic abnormalities at larval stages make it suitable for high-throughput screening




Motor impairment

Regulation of histaminergic neuron development



zinc finger nuclease; ENU-mutagenized

Hypomyelination, supernumery neuromasts, and abnormal pigmentation

Bace1 and Bace2 are proteases with different physiological functions


4. Huntington’s Disease Models

Huntington’s disease (HD) is an autosomal dominant, incurable, and fatal neurodegenerative disorder. Initially, HD patients display excessive movements of the limbs and face, and then gradually progress to exaggerated body movements described as chorea. Patients exhibit progressive symptoms, such as psychiatric, cognitive, and motor dysfunction, and this disease is usually lethal 10–20 years after the onset [87][88][89]. HD is caused by an expansion of the polyglutamine-coding region in the N-terminus of the huntingtin protein (HTT) [90]. HTT is a 350 kDa protein that is ubiquitously expressed, evolutionarily conserved, and likely to be involved in many cellular processes [91][92][93]. However, the precise mechanisms underlying the functions of the HTT gene remain incompletely understood.
The zebrafish HTT protein consists of 3121 amino acids and shares 70% identity with the human HTT orthologue [94]. Compared with the HTT-null mutation mice [92], HTT-null mutation zebrafish are viable, so the zebrafish is believed to be a suitable model to study the mechanisms of HD. To investigate the roles of HTT, several previous zebrafish HD models used MO to observe the effects of HTT deficiency in the early zebrafish development [95][96][97]. One study revealed that HTT-deficient zebrafish had hypochromic blood because of the decrease in hemoglobin production, despite the presence of iron within blood cells, and speculated that the disturbance of HTT’s normal function in the iron pathway leads to HD pathology and especially to its neuronal specificity [95]. By use of the same HTT-deficient model, Henshall et al. reported the effects of the loss-of-function of HTT on the developing nervous system and found obvious defects in the morphology of olfactory placode, neuromasts, and branchial arches, which led them to postulate that HTT may have a specific function that enables the formation of telencephalic progenitor cells and preplacodal cells in the forebrain [96]. Another study of the morpholino-based HTT loss-of-function zebrafish observed massive apoptosis of neuronal cells, accompanied by impaired neuronal development, small eyes and heads, and the enlargement of brain ventricles. Interestingly, it was observed that the expression of brain-derived neurotrophic factor (BDNF) was reduced. Notably, treatment of HTT-MO zebrafish embryos with exogenous BDNF rescued these defects, which suggests that increasing the BDNF expression might be a useful strategy for HD treatment [97].
In addition, some scientists established HD zebrafish models through the transgenic technology [98][99][100]. Schiffer et al. transiently expressed 102 polyglutamine repeats in the N-terminal fragment of the HTT protein fused with GFP (Q102-GFP) in zebrafish and found an accumulation of this mutant protein in large SDS-insoluble inclusions in the zebrafish embryos, thus reproducing an important feature of the HD pathology. The expression of the mutant HTT protein resulted in an increase in abnormal morphology and the occurrence of apoptosis in zebrafish embryos. A further study found that soluble mutant HTT protein forms are responsible for toxicity and aberrant polyglutamine aggregates in zebrafish [98]. The same study also found that its toxicity can be suppressed by the heat-shock proteins Hsp40 and Hsp70. Importantly, by the use of this HD transgenic model, two inhibitors of the Q102-GFP aggregation in vivo were identified, both of which are compounds of the N′-benzylidene-benzohydrazide class (293G02 and 306H03). In another study, a stable transgenic zebrafish line, which expressed a Q71-GFP fusion protein under the control of the rhodopsin promoter, was constructed to screen FDA-approved drugs to identify novel autophagy-inducing pathways. Three drugs (L-type Ca2+ channel antagonists, the K+ATP channel opener minoxidil, and the Gi signalling activator clonidine), which participate in a cyclical mTOR-independent pathway that regulates autophagy, were detected. This pathway has lots of candidate points to induce autophagy and reduce aggregates [99].
Cre-loxP system was also sometimes used to generate conditionally inducible transgenic zebrafish to study HD. For example, Veldman et al. created an inducible zebrafish HD model, in which the N-terminal 17 amino acids (N17) in the context of the exon 1 fragment of HTT were deleted, coupled with 97Q expansion (mHTT-ΔN17-exon1). That study found that, compared with the mHTT-ΔN17-exon1 line, fish with intact N17 and 97Q expansion (mHTT-exon1) had more delayed-onset movement deficits with slower progression. This model confirmed that the deletion of N17 terminal amino acids of the HTT will lead to an accelerated HD-like phenotype in zebrafish [100]. Recently, a separate study treated a transgenic HD zebrafish model with a phosphodiesterase 5 (PDE5) inhibitor and found an obvious decrease in the mutant HTT protein levels, cell death, and morphological abnormalities [101].

5. Other Neurodegenerative Disease Models

In addition to the above studies, zebrafish and medaka were also used in the investigation of some other rare neurodegenerative disorders. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by the motor neuron loss, and thus progressive muscle weakness and eventual death, primarily due to respiratory failure. The most prevalent genetic cause of ALS and frontotemporal dementia (FTD) is a hexanucleotide repeat expansion (HRE) within the first intron of the C9orf72 gene [102][103]. Shaw et al. generated two zebrafish lines to express C9orf72 HREs. This model recapitulates the motor deficits, cognitive impairment, muscle atrophy, motor neuron loss, and mortality in early adulthood that was observed in human C9orf72-ALS/FTD patients. Moreover, this stable transgenic model represents a powerful potential for the screening of therapeutic compounds [104]. In another study, several transgenic C9orf72-associated repeat zebrafish lines were generated by TOL2-mediated transposition. These models confirm the poly-GA toxicity in zebrafish. The reduction of poly-GA protein rescues toxicity, indicating its potential therapeutic value to treat C9orf72 repeat expansion carriers [105]. Conversely, Yeh et al. constructed two transient loss-of-function zebrafish larvae (C9orf72u-DENN, C9orf72c-DENN) using a morpholino injection. These models facilitate advances in the understanding of the functions of C9orf72 and provide potential mechanisms to elucidate the pathogenesis of ALS-FTD [106]. Mutations in the superoxide dismutase 1 (SOD1) gene were identified as another cause of ALS. In a previous study, by outcrossing the G93Ros10-SH1 line with the wildtype AB zebrafish strain, a mutant SOD1 zebrafish model was generated and used for high throughput screening to identify neuroprotective compounds [107].
Spinocerebellar ataxias (SCAs) are global neurodegenerative diseases leading to motor discoordination, which is always caused by the affected cerebellar Purkinje cells (PCs). A previous study generated a transgenic SCA type 13 (SCA13) model, which mimics a human pathological SCA13R420H mutation. This model exhibited neuropathological and behavioural changes similar to those manifested by SCA-affected patients [108]. Based on the same model, Namikawa et al. reported an SCA13-triggered cell-autonomous PC degeneration, which results in eye movement deficits [109]. In a previous study in our lab, we constructed an NPC1 knock-out zebrafish model using the CRISPR/Cas9-mediated technology [110]. This model developed symptoms similar to those observed in human patients of Niemann-Pick type C disease (NPC). We observed the loss of Purkinje cells in the cerebella of the NPC1−/− homozygous fish [110] and the aberrant motor behaviour, i.e., ataxias, a typical pathological character of human NPC1 patients (unpublished data), indicating its potential value for investigating the molecular mechanisms of NPC1.
In addition, a previous study generated a Gaucher disease (GD) model in medaka by the use of a high-resolution melting assay in the TILLING library for the glucocerebrosidase (GBA) gene [111]. In this study, it was observed that the GBAW337X/W337X (GBA−/−) medaka displayed complete deficiency in GCase activity, and it showed similar pathological phenotypes with human neuronopathic GD. Importantly, compared with the perinatal death in humans and mice lacking the GCase activity, the GBA−/− medaka survived for months, enabling the investigation of the pathological progression [111].


  1. Heemels, M.T. Neurodegenerative diseases. Nature 2016, 539, 179.
  2. Gitler, A.D.; Dhillon, P.; Shorter, J. Neurodegenerative disease: Models, mechanisms, and a new hope. Dis. Models Mech. 2017, 10, 499–502.
  3. Fernaández-Trapero, M.; Espejo-Porras, F.; Rodrıguez-Cueto, C.; Coates, J.R.; Peérez-Díaz, C.; De Lago, E.; Fernaández-Ruiz, J. Upregulation of CB2 receptors in reactive astrocytes in canine degenerative myelopathy, a disease model of amyotrophic lateral sclerosis. Dis. Model Mech. 2017, 10, 551–558.
  4. Snyder, B.R.; Chan, A.W.S. Progress in Developing Transgenic Monkey Model for Huntington’s Disease. J. Neural Transm. 2018, 125, 401–417.
  5. Story, B.D.; Miller, M.E.; Bradbury, A.M.; Million, E.D.; Duan, D.; Taghian, T.; Faissler, D.; Fernau, D.; Beecy, S.J.; Gray-Edwards, H.L. Canine Models of Inherited Musculoskeletal and Neurodegenerative Diseases. Front. Vet. Sci. 2020, 7, 80.
  6. Bolus, H.; Crocker, K.; Boekhoff-Falk, G.; Chtarbanova, S. Modeling Neurodegenerative Disorders in Drosophila melanogaster. Int. J. Mol. Sci. 2020, 21, 3055.
  7. Horzmann, K.A.; Freeman, J.L. Making waves: New developments in toxicology with the zebrafish. Toxicol. Sci. 2018, 163, 5–12.
  8. Paone, C.; Diofano, F.; Park, D.D.; Rottbauer, W.; Just, S. Genetics of cardiovascular disease: Fishing for causality. Front. Cardiovasc. Med. 2018, 5, 60.
  9. Vaz, R.L.; Outeiro, T.F.; Ferreira, J.J. Zebrafish as an animal model for drug discovery in parkinson’s disease and other movement disorders: A systematic review. Front. Neurol. 2018, 9, 347.
  10. Saleem, S.; Kannan, R.R. Zebrafish: An emerging real-time model system to study Alzheimer’s disease and neurospecific drug discovery. Cell Death Discov. 2018, 4, 45.
  11. Furutani-Seiki, M.; Wittbrodt, J. Medaka and zebrafish, an evolutionary twin study. Mech. Dev. 2004, 121, 629–637.
  12. Dang, M.; Henderson, R.E.; Garraway, L.A.; Zon, L.I. Long-term drug administration in the adult zebrafish using oral gavage for cancer preclinical studies. Dis. Model Mech. 2016, 9, 811–820.
  13. Matsuzaki, Y.; Hosokai, H.; Mizuguchi, Y.; Fukamachi, S.; Shimizu, A.; Saya, H. Establishment of HRAS(G12V) transgenic medaka as a stable tumor model for in vivo screening of anticancer drugs. PLoS ONE 2013, 8, e54424.
  14. Fior, R.; Póvoa, V.; Mendes, R.V.; Carvalho, T.; Gomes, A.; Figueiredo, N.; Ferreira, M.G. Single-cell functional and chemosensitive profiling of combinatorial colorectal therapy in zebrafish xenografts. Proc. Natl. Acad. Sci. USA 2017, 114, E8234–E8243.
  15. Howe, K.; Clark, M.D.; Torroja, C.F.; Torrance, J.; Berthelot, C.; Muffato, M.; Collins, J.E.; Humphray, S.; McLaren, K.; Matthews, L.; et al. The zebrafish reference genome sequence and its relationship to the human genome. Nature 2013, 496, 498–503.
  16. Apfeld, J.; Alper, S. What Can We Learn About Human Disease from the Nematode C. elegans? Methods Mol. Biol. 2018, 1706, 53–75.
  17. Yamaguchi, M.; Yoshida, H. Drosophila as a Model Organism. Adv. Exp. Med. Biol. 2018, 1076, 1–10.
  18. Kim, S.S.; Im, S.H.; Yang, J.Y.; Lee, Y.R.; Kim, G.R.; Chae, J.S.; Shin, D.S.; Song, J.S.; Ahn, S.; Lee, B.H.; et al. Zebrafish as a Screening Model for Testing the Permeability of Blood-Brain Barrier to Small Molecules. Zebrafish 2017, 14, 322–330.
  19. Panula, P.; Chen, Y.C.; Priyadarshini, M.; Kudo, H.; Semenova, S.; Sundvik, M.; Sallinen, V. The comparative neuroanatomy and neurochemistry of zebrafish CNS systems of relevance to human neuropsychiatric diseases. Neurobiol. Dis. 2010, 40, 46–57.
  20. Matsui, H.; Uemura, N.; Yamakado, H.; Takeda, S.; Takahashi, R. Exploring the pathogenetic mechanisms underlying Parkinson’s disease in medaka fish. J. Parkinsons Dis. 2014, 4, 301–310.
  21. Wittbrodt, J.; Shima, A.; Schartl, M. Medaka—a model organism from the Far East. Nat. Rev. Genet. 2002, 3, 53–64.
  22. Stewart, A.M.; Braubach, O.; Spitsbergen, J.; Gerlai, R.; Kalueff, A.V. Zebrafish models for translational neuroscience research: From tank to bedside. Trends Neurosci. 2014, 37, 264–278.
  23. GBD 2016 Parkinson’s Disease Collaborators. Global, regional, and national burden of Parkinson’s disease, 1990-2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2018, 17, 939–953.
  24. Savica, R.; Grossardt, B.R.; Bower, J.H.; Ahlskog, J.E.; Boeve, B.F.; Graff-Radford, J.; Rocca, W.A.; Mielke, M.M. Survival and Causes of Death among People with Clinically Diagnosed Synucleinopathies with Parkinsonism: A Population-Based Study. JAMA Neurol. 2017, 74, 839–846.
  25. Darweesh, S.K.L.; Raphael, K.G.; Brundin, P.; Matthews, H.; Wyse, R.K.; Chen, H.; Bloem, B.R. Parkinson Matters. J. Parkinsons Dis. 2018, 8, 495–498.
  26. James, S.L.; Abate, D.; Abate, K.H.; Abay, S.M.; Abbafati, C.; Abbasi, N.; Abbastabar, H.; Abd-Allah, F.; Abdela, J.; Abdelalim, A.; et al. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018, 392, 1789–1858.
  27. Roth, G.A.; Abate, D.; Abate, K.H.; Abay, S.M.; Abbafati, C.; Abbasi, N.; Abbastabar, H.; Abd-Allah, F.; Abdela, J.; Abdelalim, A.; et al. Global, Regional, and National Age-Sex-Specific Mortality for 282 Causes of Death in 195 Countries and Territories, 1980–2017: A Systematic Analysis for the Global Burden of Disease Study 2017. Lancet 2018, 392, 1736–1788.
  28. Rocca, W.A. The burden of Parkinson’s disease: A worldwide perspective. Lancet Neurol. 2018, 17, 928–929.
  29. Pirtošek, Z.; Bajenaru, O.; Kovács, N.; Milanov, I.; Relja, M.; Skorvanek, M. Update on the Management of Parkinson’s Disease for General Neurologists. Parkinson’s Dis. 2020, 2020, 9131474.
  30. Hoo, J.Y.; Kumari, Y.; Shaikh, M.F.; Hue, S.M.; Goh, B.H. Zebrafish: A Versatile Animal Model for Fertility Research. BioMed Res. Int. 2016, 2016, 9732780.
  31. Rahman Khan, F.; Sulaiman Alhewairini, S. Zebrafish (Danio rerio) as a Model Organism. Curr. Trends Cancer Manag. 2019, 2019, 81517.
  32. Matsui, H.; Takahashi, R. Parkinson’s disease pathogenesis from the viewpoint of small fish models. J. Neural Transm. 2018, 125, 25–33.
  33. Barnhill, L.M.; Murata, H.; Bronstein, J.M. Studying the pathophysiology of Parkinson’s disease using zebrafish. Biomedicines 2020, 8, 8070197.
  34. Lam, C.S.; Korzh, V.; Strahle, U. Zebrafish embryos are susceptible to the dopaminergic neurotoxin MPTP. Eur. J. Neurosci. 2005, 21, 1758–1762.
  35. Wasel, O.; Freeman, J.L. Chemical and genetic zebrafish models to define mechanisms of and treatments for dopaminergic neurodegeneration. Int. J. Mol. Sci. 2020, 21, 5981.
  36. Sarath, B.N.; Murthy, C.H.L.; Kakara, S.; Sharma, R.; Brahmendra, S.C.V.; Idris, M.M. 1-Methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine induced Parkinson’s disease in zebrafish. Proteomics 2016, 16, 1407–1420.
  37. Vijayanathan, Y.; Lim, F.T.; Lim, S.M.; Long, C.M.; Tan, M.P.; Majeed, A.B.A.; Ramasamy, K. 6-OHDA-Lesioned Adult Zebrafish as a Useful Parkinson’s Disease Model for Dopaminergic Neuroregeneration. Neurotox. Res. 2017, 32, 496–508.
  38. Vaz, R.L.; Sousa, S.; Chapela, D.; van der Linde, H.C.; Willemsen, R.; Correia, A.D.; Outeiro, T.F.; Afonso, N.D. Identification of antiparkinsonian drugs in the 6-hydroxydopamine zebrafish model. Pharmacol. Biochem. Behav. 2020, 189, 172828.
  39. Li, M.; Zhou, F.; Xu, T.; Song, H.; Lu, B. Acteoside protects against 6-OHDA-induced dopaminergic neuron damage via Nrf2-ARE signaling pathway. Food Chem. Toxicol. 2018, 119, 6–13.
  40. Cronin, A.; Grealy, M. Neuroprotective and neuro-restorative effects of minocycline and rasagiline in a zebrafish 6-hydroxydopamine model of Parkinson’s disease. Neuroscience 2017, 367, 34–46.
  41. Wang, X.H.; Souders, C.L.; Zhao, Y.H.; Martyniuk, C.J. Paraquat affects mitochondrial bioenergetics, dopamine system expression, and locomotor activity in zebrafish (Danio rerio). Chemosphere 2018, 191, 106–117.
  42. Nellore, J.P.N. Paraquat exposure induces behavioral deficits in larval zebrafish during the window of dopamine neurogenesis. Toxicol. Rep. 2015, 2, 950–956.
  43. Bortolotto, J.W.; Cognato, G.P.; Christoff, R.R.; Roesler, L.N.; Leite, C.E.; Kist, L.W.; Bogo, M.R.; Vianna, M.R.; Bonan, C.D. Long-term exposure to paraquat alters behavioral parameters and dopamine levels in adult zebrafish (Danio rerio). Zebrafish 2014, 11, 142–153.
  44. Müller, T.E.; Nunes, M.E.; Menezes, C.C.; Marins, A.T.; Leitemperger, J.; Gressler, A.C.L.; Carvalho, F.B.; de Freitas, C.M.; Quadros, V.A.; Fachinetto, R.; et al. Sodium Selenite Prevents Paraquat-Induced Neurotoxicity in Zebrafish. Mol. Neurobiol. 2018, 55, 1928–1941.
  45. Lv, D.J.; Li, L.X.; Chen, J.; Wei, S.Z.; Wang, F.; Hu, H.; Xie, A.M.; Liu, C.F. Sleep deprivation caused a memory defects and emotional changes in a rotenone-based zebrafish model of Parkinson’s disease. Behav. Brain Res. 2019, 372, 112031.
  46. Ramli, M.D.B.C.; Hashim, N.H.B.; Uzid, M.B.M.; Weinheimeri, A.Z. Zebrafish parkinson’s model: The effects of tocotrienol rich fraction towards rotenone induced zebrafish. Int. J. Med. Toxicol. Legal Med. 2020, 23, 1–7.
  47. Ünal, İ.; Üstündağ, Ü.V.; Ateş, P.S.; Eğilmezer, G.; Alturfan, A.A.; Yiğitbaşı, T.; Emekli-Alturfan, E. Rotenone impairs oxidant/antioxidant balance both in brain and intestines in zebrafish. Int. J. Neurosci. 2019, 129, 363–368.
  48. Wang, Q.; Liu, Y.; Zhou, J. Neuroinflammation in Parkinson’s disease and its potential as therapeutic target. Trans. Neurodegener. 2015, 4, 40–42.
  49. Ge, P.; Dawson, V.L.; Dawson, T.M. PINK1 and Parkin mitochondrial quality control: A source of regional vulnerability in Parkinson’s disease. Mole Neurodegener. 2020, 15, 7.
  50. Flinn, L.; Mortiboys, H.; Volkmann, K.; Kster, R.W.; Ingham, P.W.; Bandmann, O. Complex I deficiency and dopaminergic neuronal cell loss in parkin-deficient zebrafish (Danio rerio). Brain 2009, 132, 1613–1623.
  51. Sallinen, V.; Kolehmainen, J.; Priyadarshini, M.; Toleikyte, G.; Chen, Y.C.; Panula, P. Dopaminergic cell damage and vulnerability to MPTP in PINK1 knockdown zebrafish. Neurobiol. Dis. 2010, 40, 93–101.
  52. Xi, Y.; Ryan, J.; Noble, S.; Yu, M.; Yilbas, A.E.; Ekker, M. Impaired dopaminergic neuron development and locomotor function in zebrafish with loss of pink1 function. Eur. J. Neurosci. 2010, 31, 623–633.
  53. Sloan, M.; Alegre-Abarrategui, J.; Wade-Martins, R. Insights into LRRK2 function and dysfunction from transgenic and knockout rodent models. Biochem. Soc. Trans. 2012, 40, 1080–1085.
  54. Prabhudesai, S.; Bensabeur, F.Z.; Abdullah, R.; Basak, I.; Baez, S.; Alves, G.; Holtzman, N.G.; Larsen, J.P.; Møller, S.G. LRRK2 knockdown in zebrafish causes developmental defects, neuronal loss, and synuclein aggregation. J. Neurosci. Res. 2016, 94, 17–35.
  55. Sheng, D.; Qu, D.; Kwok, K.H.; Ng, S.S.; Lim, A.Y.; Aw, S.S.; Lee, C.W.; Sung, W.K.; Tan, E.K.; Lufkin, T.; et al. Deletion of the WD40 domain of LRRK2 in Zebrafish causes Parkinsonism-like loss of neurons and locomotive defect. PLoS Genet. 2010, 6, e1000914.
  56. Seegobin, S.P.; Heaton, G.R.; Liang, D.; Choi, I.; Blanca Ramirez, M.; Tang, B.; Yue, Z. Progress in LRRK2-Associated Parkinson’s Disease Animal Models. Front. Neurosci. 2020, 14, 674.
  57. Hughes, G.L.; Lones, M.A.; Bedder, M.; Currie, P.D.; Smith, S.L.; Pownall, M.E. Machine learning discriminates a movement disorder in a zebrafish model of Parkinson’s disease. Dis. Model Mech. 2020, 13, dmm045815.
  58. Bai, Q.; Mullett, S.J.; Garver, J.A.; Hinkle, D.A.; Burton, E.A. Zebrafish DJ-1 is evolutionarily conserved and expressed in dopaminergic neurons. Brain Res. 2006, 1113, 33–44.
  59. Bretaud, S.; Allen, C.; Ingham, P.W.; Bandmann, O. p53-dependent neuronal cell death in a DJ-1-deficient zebrafish model of Parkinson’s disease. J. Neurochem. 2007, 100, 1626–1635.
  60. Edson, A.J.; Hushagen, H.A.; Frøyset, A.K.; Elda, I.; Khan, E.A.; Di Stefano, A.; Fladmark, K.E. Dysregulation in the Brain Protein Profile of Zebrafish Lacking the Parkinson’s Disease-Related Protein DJ-1. Mol. Neurobiol. 2019, 56, 8306–8322.
  61. O’Donnell, K.C.; Lulla, A.; Stahl, M.C.; Wheat, N.D.; Bronstein, J.M.; Sagasti, A. Axon degeneration and PGC-1a-mediated protection in a zebrafish model of a-synuclein toxicity. Dis. Models Mech. 2014, 7, 571–582.
  62. Keatinge, M.; Bui, H.; Menke, A.; Chen, Y.C.; Sokol, A.M.; Bai, Q.; Ellett, F.; Da Costa, M.; Burke, D.; Gegg, M.; et al. Glucocerebrosidase 1 deficient Danio rerio mirror key pathological aspects of human Gaucher disease and provide evidence of early microglial activation preceding alpha-synuclein-independent neuronal cell death. Hum. Mol. Genet. 2015, 24, 6640–6652.
  63. Matsui, H.; Ito, J.; Matsui, N.; Uechi, T.; Onodera, O.; Kakita, A. Cytosolic dsDNA of mitochondrial origin induces cytotoxicity and neurodegeneration in cellular and zebrafish models of Parkinson’s disease. Nat. Commun. 2021, 12, 3101.
  64. Noble, S.; Ismail, A.; Godoy, R.; Xi, Y.; Ekker, M. Zebrafish Parla- and Parlb-deficiency affects dopaminergic neuron patterning and embryonic survival. J. Neurochem. 2012, 122, 196–207.
  65. Merhi, R.; Kalyn, M.; Zhu-Pawlowsky, A.; Ekker, M. Loss of parla Function Results in Inactivity, Olfactory Impairment, and Dopamine Neuron Loss in Zebrafish. Biomedicines 2021, 9, 205.
  66. Alzheimer’s Association. 2020 Alzheimer’s disease facts and figures. Alzheimer’s Dement. 2020, 16, 391–460.
  67. Alzheimer’s Disease International. World Alzheimer Report 2019: Attitudes to Dementia; Alzheimer’s Disease International (ADI): London, UK, 2019.
  68. Vaz, M.; Silvestre, S. Alzheimer’s disease: Recent treatment strategies. Eur. J. Pharmacol. 2020, 887, 173554.
  69. Breijyeh, Z.; Karaman, R. Comprehensive Review on Alzheimer’s Disease: Causes and Treatment. Molecules 2020, 25, 5789.
  70. Cummings, J.L.; Cohen, S.; van Dyck, C.H.; Brody, M.; Curtis, C.; Cho, W.; Ward, M.; Friesenhahn, M.; Rabe, C.; Brunstein, F.; et al. ABBY: A phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease. Neurology 2018, 90, e1889–e1897.
  71. Alzheimer’s Association. 2018 Alzheimer’s disease facts and figures. Alzheimers Dement. 2018, 14, 367–429.
  72. Ruhl, T.; Jonas, A.; Seidel, N.I.; Prinz, N.; Albayram, O.; Bilkei-Gorzo, A.; von der Emde, G. Oxidation and Cognitive Impairment in the Aging Zebrafish. Gerontology 2015, 62, 47–57.
  73. Bhattarai, P.; Thomas, A.K.; Cosacak, M.I.; Papadimitriou, C.; Mashkaryan, V.; Zhang, Y.; Kizil, C. Modeling Amyloid-β42 Toxicity and Neurodegeneration in Adult Zebrafish Brain. J. Vis. Exp. 2017, 128, 56014.
  74. Bhattarai, P.; Thomas, A.K.; Zhang, Y.; Kizil, C. The effects of aging on Amyloid-β42-induced neurodegeneration and regeneration in adult zebrafish brain. Neurogenesis 2017, 4, e1322666.
  75. Rudrabhatla, P.; Pant, H.C. Role of protein phosphatase 2A in Alzheimer’s disease. Curr. Alzheimer Res. 2011, 8, 623–632.
  76. Nada, S.E.; Williams, F.E.; Shah, Z.A. Development of a Novel and Robust Pharmacological Model of Okadaic Acid-induced Alzheimer’s Disease in Zebrafish. CNS Neurol. Disord. Drug Targets 2016, 15, 86–94.
  77. Koehler, D.; Williams, F.E. Utilizing zebrafish and okadaic acid to study Alzheimer’s disease. Neural Regen. Res. 2018, 13, 1538–1541.
  78. Muthuraman, A.; Thilagavathi, L.; Jabeen, S.; Ravishankar, S.B.; Ahmed, S.S.; George, T.; Rishitha, N.; Paramakrishnan, N. Curcumin prevents cigarette smoke extract induced cognitive impairment. Front. Biosci. 2019, 11, 109–120.
  79. Muthuraman, A.; Nafisa, K.; Sowmya, M.S.; Arpitha, B.M.; Choedon, N.; Sandy, C.D.; Rishitha, N.; Johurul, I. Role of ambrisentan (selective endothelin-A receptor antagonist) on cigarette smoke exposure induced cognitive impairment in Danio rerio. Life Sci. 2019, 222, 133–139.
  80. He, X.; Zhong, Z.M.; Che, Y. Locomotor activity and learning and memory abilities in Alzheimer’s disease induced by aluminum in an acid environment in zebrafish. Dongwuxue Yanjiu 2012, 33, 231–236.
  81. Acosta, D.D.S.; Danielle, N.M.; Altenhofen, S.; Luzardo, M.D.; Costa, P.G.; Bianchini, A.; Bonan, C.D.; da Silva, R.S.; Dafre, A.L. Copper at low levels impairs memory of adult zebrafish (Danio rerio) and affects swimming performance of larvae. Comp. Biochem. Physiol. C Toxicol. Pharmacol. 2016, 185–186, 122–130.
  82. Altenhofen, S.; Wiprich, M.T.; Nery, L.R.; Leite, C.E.; Vianna, M.R.M.R.; Bonan, C.D. Manganese(II) chloride alters behavioral and neurochemical parameters in larvae and adult zebrafish. Aquat. Toxicol. 2017, 182, 172–183.
  83. Bai, Q.; Garver, J.A.; Hukriede, N.A.; Burton, E.A. Generation of a transgenic zebrafish model of Tauopathy using a novel promoter element derived from the zebrafish eno2 gene. Nucleic Acids Res. 2007, 35, 6501–6516.
  84. Paquet, D.; Bhat, R.; Sydow, A.; Mandelkow, E.M.; Berg, S.; Hellberg, S.; Fälting, J.; Distel, M.; Köster, R.W.; Schmid, B.; et al. A zebrafish model of tauopathy allows in vivo imaging of neuronal cell death and drug evaluation. J. Clin. Investig. 2009, 119, 1382–1395.
  85. Sundvik, M.; Chen, Y.C.; Panula, P. Presenilin1 regulates histamine neuron development and behavior in zebrafish, danio rerio. J. Neurosci. 2013, 33, 1589–1597.
  86. van Bebber, F.; Hruscha, A.; Willem, M.; Schmid, B.; Haass, C. Loss of Bace2 in zebrafish affects melanocyte migration and is distinct from Bace1 knock out phenotypes. J. Neurochem. 2013, 127, 471–481.
  87. Shannon, K.M. Huntington’s disease—Clinical signs, symptoms, presymptomatic diagnosis, and diagnosis. Handb. Clin. Neurol. 2011, 100, 3–13.
  88. Ross, C.A.; Aylward, E.H.; Wild, E.J.; Langbehn, D.R.; Long, J.D.; Warner, J.H.; Scahill, R.I.; Leavitt, B.R.; Stout, J.C.; Paulsen, J.S.; et al. Huntington disease: Natural history, biomarkers and prospects for therapeutics. Nat. Rev. Neurol. 2014, 10, 204–216.
  89. Walker, F.O. Huntington’s disease. Lancet 2007, 369, 218–228.
  90. The Huntington’s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 1993, 72, 971–983.
  91. Duyao, M.P.; Auerbach, A.B.; Ryan, A.; Persichetti, F.; Barnes, G.T.; McNeil, S.M.; Ge, P.; Vonsattel, J.P.; Gusella, J.F.; Joyner, A.L.; et al. Inactivation of the mouse Huntington’s disease gene homolog Hdh. Science 1995, 269, 407–410.
  92. Zeitlin, S.; Liu, J.P.; Chapman, D.L.; Papaioannou, V.E.; Efstratiadis, A. Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington’s disease gene homologue. Nat. Genet. 1995, 11, 155–163.
  93. Nasir, J.; Floresco, S.B.; O’Kusky, J.R.; Diewert, V.M.; Richman, J.M.; Zeisler, J.; Borowski, A.; Marth, J.D.; Phillips, A.G.; Hayden, M.R. Targeted disruption of the Huntington’s disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell 1995, 81, 811–823.
  94. Karlovich, C.A.; John, R.M.; Ramirez, L.; Stainier, D.Y.; Myers, R.M. Characterization of the Huntington’s disease (HD) gene homologue in the zebrafish Danio rerio. Gene 1998, 217, 117–125.
  95. Lumsden, A.L.; Henshall, T.L.; Dayan, S.; Lardelli, M.T.; Richards, R.I. Huntingtin-deficient zebrafish exhibit defects in iron utilization and development. Hum. Mol. Genet. 2007, 16, 1905–1920.
  96. Henshall, T.L.; Tucker, B.; Lumsden, A.L.; Nornes, S.; Lardelli, M.T.; Richards, R.I. Selective neuronal requirement for huntingtin in the developing zebrafish. Hum. Mol. Genet. 2009, 18, 4830–4842.
  97. Diekmann, H.; Anichtchik, O.; Fleming, A.; Futter, M.; Goldsmith, P.; Roach, A.; Rubinsztein, D.C. Decreased BDNF levels are a major contributor to the embryonic phenotype of huntingtin knockdown zebrafish. J. Neurosci. 2009, 29, 1343–1349.
  98. Schiffer, N.W.; Broadley, S.A.; Hirschberger, T.; Tavan, P.; Kretzschmar, H.A.; Giese, A.; Haass, C.; Hartl, F.U.; Schmid, B. Identification of anti-prion compounds as efficient inhibitors of polyglutamine protein aggregation in a zebrafish model. J. Biol. Chem. 2007, 282, 9195–9203.
  99. Williams, A.; Sarkar, S.; Cuddon, P.; Ttofi, E.K.; Saiki, S.; Siddiqi, F.H.; Jahreiss, L.; Fleming, A.; Pask, D.; Goldsmith, P.; et al. Novel targets for Huntington’s disease in an mTOR-independent autophagy pathway. Nat. Chem. Biol. 2008, 4, 295–305.
  100. Veldman, M.B.; Rios-Galdamez, Y.; Lu, X.H.; Gu, X.; Qin, W.; Li, S.; Yang, X.W.; Lin, S. The N17 domain mitigates nuclear toxicity in a novel zebrafish Huntington’s disease model. Mol. Neurodegener. 2015, 10, 67.
  101. VerPlank, J.J.S.; Tyrkalska, S.D.; Fleming, A.; Rubinsztein, D.C.; Goldberg, A.L. cGMP via PKG activates 26S proteasomes and enhances degradation of proteins, including ones that cause neurodegenerative diseases. Proc. Natl. Acad. Sci. USA 2020, 117, 14220–14230.
  102. Renton, A.E.; Majounie, E.; Waite, A.; Simon-Sanchez, J.; Rollinson, S.; Gibbs, J.R.; Schymick, J.C.; Laaksovirta, H.; van Swieten, J.C.; Myllykangas, L.; et al. A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD. Neuron 2011, 72, 257–268.
  103. Sullivan, P.M.; Zhou, X.; Robins, A.M.; Paushter, D.H.; Kim, D.; Smolka, M.B.; Hu, F. The ALS/FTLD associated protein C9orf72 associates with SMCR8 and WDR41 to regulate the autophagy-lysosome pathway. Acta Neuropathol. Commun. 2016, 4, 51.
  104. Shaw, M.P.; Higginbottom, A.; McGown, A.; Castelli, L.M.; James, E.; Hautbergue, G.M.; Shaw, P.J.; Ramesh, T.M. Stable transgenic C9orf72 zebrafish model key aspects of the ALS/FTD phenotype and reveal novel pathological features. Acta Neuropathol. Commun. 2018, 6, 125.
  105. Ohki, Y.; Wenninger-Weinzierl, A.; Hruscha, A.; Asakawa, K.; Kawakami, K.; Haass, C.; Edbauer, D.; Schmid, B. Glycine-alanine dipeptide repeat protein contributes to toxicity in a zebrafish model of C9orf72 associated neurodegeneration. Mol. Neurodegener. 2017, 12, 6.
  106. Yeh, T.H.; Liu, H.F.; Li, Y.W.; Lu, C.S.; Shih, H.Y.; Chiu, C.C.; Lin, S.J.; Huang, Y.C.; Cheng, Y.C. C9orf72 is essential for neurodevelopment and motility mediated by Cyclin G1. Exp. Neurol. 2018, 304, 114–124.
  107. McGown, A.; Shaw, D.P.J.; Ramesh, T. ZNStress: A high-throughput drug screening protocol for identification of compounds modulating neuronal stress in the transgenic mutant sod1G93R zebrafish model of amyotrophic lateral sclerosis. Mol. Neurodegener. 2016, 11, 56.
  108. Namikawa, K.; Dorigo, A.; Zagrebelsky, M.; Russo, G.; Kirmann, T.; Fahr, W.; Dübel, S.; Korte, M.; Köster, R.W. Modeling Neurodegenerative Spinocerebellar Ataxia Type 13 in Zebrafish Using a Purkinje Neuron Specific Tunable Coexpression System. J. Neurosci. 2019, 39, 3948–3969.
  109. Namikawa, K.; Dorigo, A.; Köster, R.W. Neurological Disease Modelling for Spinocerebellar Ataxia Using Zebrafish. J. Exp. Neurosci. 2019, 13, 1179069519880515.
  110. Lin, Y.; Cai, X.; Wang, G.; Ouyang, G.; Cao, H. Model construction of Niemann-Pick type C disease in zebrafish. Biol. Chem. 2018, 399, 903–910.
  111. Uemura, N.; Koike, M.; Ansai, S.; Kinoshita, M.; Ishikawa-Fujiwara, T.; Matsui, H.; Naruse, K.; Sakamoto, N.; Uchiyama, Y.; Todo, T.; et al. Viable neuronopathic Gaucher disease model in Medaka (Oryzias latipes) displays axonal accumulation of alpha-synuclein. PLoS Genet. 2015, 11, e1005065.
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to :
View Times: 291
Revisions: 2 times (View History)
Update Date: 22 Oct 2021