Nonmammalian Models for Neurodegenerative and Neurological Disorders

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 18188

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Guest Editor
Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, VIC 3086, Australia
Interests: mitochondrial biology and disease; neurodegenerative disease; AMPK; TOR complex I; cellular stress signalling
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Guest Editor
Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, VIC 3086, Australia
Interests: mitochondria; neurodegenerative disease; Parkinson’s disease; myalgic encephalomyelitis/chronic fatigue syndrome; long COVID; Dictyostelium discoideum
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Within two decades, neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease are expected collectively to surpass cancer as the 2nd highest worldwide cause of mortality. Understanding them and other diseases of the central nervous system presents special challenges because of the complexity and relative inaccessibility of the mammalian brain. Because of these challenges, nonmammalian model organisms continue to provide opportunities to study these diseases in simpler, more experimentally tractable systems than the mammalian nervous system. Having contributed to more than half of the Nobel Prizes in Physiology and Medicine over the past two decades, nonmammalian models have a proven track record in driving fundamental advances in understanding disease. Their well-studied genetics and ease of manipulation makes them ideal for studying the function of disease-associated genes/proteins, their interactions and their roles in disease-associated signalling pathways. As they can be relatively cheaply maintained, develop rapidly and produce large numbers of offspring, these models are extremely useful in the high-throughput screening and testing of therapeutic agents.

This Special Issue aims to celebrate and illuminate the contributions of nonmammalian model systems to our growing understanding of neurodegenerative and neurological diseases. The relevant model systems may include eukaryotic microbes such as yeast and protozoa, invertebrate animals such as sea slugs, sea urchins, nematodes and flies; and nonmammalian vertebrates such as zebrafish. Both focused review articles and original research papers are welcome contributions.

Dr. Paul Fisher
Dr. Sarah Annesley
Guest Editors

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Keywords

  • neurodegenerative diseases
  • mitochondria
  • non-mammalian models
  • Parkinson’s disease
  • Alzheimer’s disease
  • Huntington’s disease
  • mucolipidosis
  • Rett syndrome
  • yeast
  • zebrafish
  • Drosophila
  • Xenopus
  • nematodes

Published Papers (6 papers)

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Research

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17 pages, 2315 KiB  
Article
Decanoic Acid Stimulates Autophagy in D. discoideum
by Eleanor C. Warren, Pavol Kramár, Katie Lloyd-Jones and Robin S. B. Williams
Cells 2021, 10(11), 2946; https://doi.org/10.3390/cells10112946 - 29 Oct 2021
Cited by 5 | Viewed by 2721
Abstract
Ketogenic diets, used in epilepsy treatment, are considered to work through reduced glucose and ketone generation to regulate a range of cellular process including autophagy induction. Recent studies into the medium-chain triglyceride (MCT) ketogenic diet have suggested that medium-chain fatty acids (MCFAs) provided [...] Read more.
Ketogenic diets, used in epilepsy treatment, are considered to work through reduced glucose and ketone generation to regulate a range of cellular process including autophagy induction. Recent studies into the medium-chain triglyceride (MCT) ketogenic diet have suggested that medium-chain fatty acids (MCFAs) provided in the diet, decanoic acid and octanoic acid, cause specific therapeutic effects independent of glucose reduction, although a role in autophagy has not been investigated. Both autophagy and MCFAs have been widely studied in Dictyostelium, with findings providing important advances in the study of autophagy-related pathologies such as neurodegenerative diseases. Here, we utilize this model to analyze a role for MCFAs in regulating autophagy. We show that treatment with decanoic acid but not octanoic acid induces autophagosome formation and modulates autophagic flux in high glucose conditions. To investigate this effect, decanoic acid, but not octanoic acid, was found to induce the expression of autophagy-inducing proteins (Atg1 and Atg8), providing a mechanism for this effect. Finally, we demonstrate a range of related fatty acid derivatives with seizure control activity, 4BCCA, 4EOA, and Epilim (valproic acid), also function to induce autophagosome formation in this model. Thus, our data suggest that decanoic acid and related compounds may provide a less-restrictive therapeutic approach to activate autophagy. Full article
(This article belongs to the Special Issue Nonmammalian Models for Neurodegenerative and Neurological Disorders)
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17 pages, 1987 KiB  
Article
Assessment and Validation of Globodera pallida as a Novel In Vivo Model for Studying Alzheimer’s Disease
by Norah A. Althobaiti, Farid Menaa, Aishah E. Albalawi, Johnathan J. Dalzell, Neil D. Warnock, Erin M. Mccammick, Abdulellah Alsolais, Abeer M. Alkhaibari and Brian D. Green
Cells 2021, 10(9), 2481; https://doi.org/10.3390/cells10092481 - 19 Sep 2021
Cited by 4 | Viewed by 2486
Abstract
Background: Whole transgenic or non-transgenic organism model systems allow the screening of pharmacological compounds for protective actions in Alzheimer’s disease (AD). Aim: In this study, a plant parasitic nematode, Globodera pallida, which assimilates intact peptides from the external environment, was investigated as [...] Read more.
Background: Whole transgenic or non-transgenic organism model systems allow the screening of pharmacological compounds for protective actions in Alzheimer’s disease (AD). Aim: In this study, a plant parasitic nematode, Globodera pallida, which assimilates intact peptides from the external environment, was investigated as a new potential non-transgenic model system of AD. Methods: Fresh second-stage juveniles of G. pallida were used to measure their chemosensory, perform immunocytochemistry on their neurological structures, evaluate their survival rate, measure reactive oxygen species, and determine total oxidized glutathione to reduced glutathione ratio (GSSG/GSH) levels, before and after treatment with 100 µM of various amyloid beta (Aβ) peptides (1–40, 1–42, 17–42, 17–40, 1–28, or 1–16). Wild-type N2 C. elegans (strain N2) was cultured on Nematode Growth Medium and directly used, as control, for chemosensory assays. Results: We demonstrated that: (i) G. pallida (unlike Caenorhabditis elegans) assimilates amyloid-β (Aβ) peptides which co-localise with its neurological structures; (ii) pre-treatment with various Aβ isoforms (1–40, 1–42, 17–42, 17–40, 1–28, or 1–16) impairs G. pallida’s chemotaxis to differing extents; (iii) Aβ peptides reduced survival, increased the production of ROS, and increased GSSG/GSH levels in this model; (iv) this unique model can distinguish differences between different treatment concentrations, durations, and modalities, displaying good sensitivity; (v) clinically approved neuroprotective agents were effective in protecting G. pallida from Aβ (1–42) exposure. Taken together, the data indicate that G. pallida is an interesting in vivo model with strong potential for discovery of novel bioactive compounds with anti-AD activity. Full article
(This article belongs to the Special Issue Nonmammalian Models for Neurodegenerative and Neurological Disorders)
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30 pages, 8259 KiB  
Article
α-Synuclein Decreases the Abundance of Proteasome Subunits and Alters Ubiquitin Conjugates in Yeast
by Blagovesta Popova, Dajana Galka, Nicola Häffner, Dan Wang, Kerstin Schmitt, Oliver Valerius, Michael Knop and Gerhard H. Braus
Cells 2021, 10(9), 2229; https://doi.org/10.3390/cells10092229 - 28 Aug 2021
Cited by 5 | Viewed by 3056
Abstract
Parkinson’s disease (PD) is the most prevalent movement disorder characterized with loss of dopaminergic neurons in the brain. One of the pathological hallmarks of the disease is accumulation of aggregated α-synuclein (αSyn) in cytoplasmic Lewy body inclusions that indicates significant dysfunction of protein [...] Read more.
Parkinson’s disease (PD) is the most prevalent movement disorder characterized with loss of dopaminergic neurons in the brain. One of the pathological hallmarks of the disease is accumulation of aggregated α-synuclein (αSyn) in cytoplasmic Lewy body inclusions that indicates significant dysfunction of protein homeostasis in PD. Accumulation is accompanied with highly elevated S129 phosphorylation, suggesting that this posttranslational modification is linked to pathogenicity and altered αSyn inclusion dynamics. To address the role of S129 phosphorylation on protein dynamics further we investigated the wild type and S129A variants using yeast and a tandem fluorescent timer protein reporter approach to monitor protein turnover and stability. Overexpression of both variants leads to inhibited yeast growth. Soluble S129A is more stable and additional Y133F substitution permits αSyn degradation in a phosphorylation-independent manner. Quantitative cellular proteomics revealed significant αSyn-dependent disturbances of the cellular protein homeostasis, which are increased upon S129 phosphorylation. Disturbances are characterized by decreased abundance of the ubiquitin-dependent protein degradation machinery. Biotin proximity labelling revealed that αSyn interacts with the Rpt2 base subunit. Proteasome subunit depletion by reducing the expression of the corresponding genes enhances αSyn toxicity. Our studies demonstrate that turnover of αSyn and depletion of the proteasome pool correlate in a complex relationship between altered proteasome composition and increased αSyn toxicity. Full article
(This article belongs to the Special Issue Nonmammalian Models for Neurodegenerative and Neurological Disorders)
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15 pages, 5498 KiB  
Article
Identifying the Effects of Reactive Oxygen Species on Mitochondrial Dynamics and Cytoskeleton Stability in Dictyostelium discoideum
by Evan Downs, Amber D. Bottrell and Kari Naylor
Cells 2021, 10(8), 2147; https://doi.org/10.3390/cells10082147 - 20 Aug 2021
Cited by 3 | Viewed by 2136
Abstract
Defects in mitochondrial dynamics, fission, fusion, and motility have been implicated in the pathogenesis of multiple neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and Charcot–Marie–Tooth disease. Another key feature of neurodegeneration is the increase in reactive oxygen species (ROS). Previous work [...] Read more.
Defects in mitochondrial dynamics, fission, fusion, and motility have been implicated in the pathogenesis of multiple neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and Charcot–Marie–Tooth disease. Another key feature of neurodegeneration is the increase in reactive oxygen species (ROS). Previous work has shown that the cytoskeleton, in particular the microtubules, and ROS generated by rotenone significantly regulate mitochondrial dynamics in Dictyostelium discoideum. The goal of this project is to study the effects of ROS on mitochondrial dynamics within our model organism D. discoideum to further understand the underlying issues that are the root of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. We chose three likely ROS inducers, cumene hydroperoxide, hydroxylamine hydrochloride, and Antimycin A. Our work demonstrates that alteration of the microtubule cytoskeleton is not required to alter dynamics in response to ROS and there is no easy way to predict how mitochondrial dynamics will be altered based on which ROS generator is used. This research contributes to the better understanding of the cellular mechanisms that induce the pathogenesis of incurable neurodegenerative diseases with the hope that it will translate into developing new and more effective treatments for patients afflicted by them. Full article
(This article belongs to the Special Issue Nonmammalian Models for Neurodegenerative and Neurological Disorders)
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25 pages, 3739 KiB  
Article
Cytotoxicity and Mitochondrial Dysregulation Caused by α-Synuclein in Dictyostelium discoideum
by Sanjanie Fernando, Claire Y. Allan, Katelyn Mroczek, Xavier Pearce, Oana Sanislav, Paul R. Fisher and Sarah J. Annesley
Cells 2020, 9(10), 2289; https://doi.org/10.3390/cells9102289 - 14 Oct 2020
Cited by 9 | Viewed by 2871
Abstract
Alpha synuclein has been linked to both sporadic and familial forms of Parkinson’s disease (PD) and is the most abundant protein in Lewy bodies a hallmark of Parkinson’s disease. The function of this protein and the molecular mechanisms underlying its toxicity are still [...] Read more.
Alpha synuclein has been linked to both sporadic and familial forms of Parkinson’s disease (PD) and is the most abundant protein in Lewy bodies a hallmark of Parkinson’s disease. The function of this protein and the molecular mechanisms underlying its toxicity are still unclear, but many studies have suggested that the mechanism of α-synuclein toxicity involves alterations to mitochondrial function. Here we expressed human α-synuclein and two PD-causing α-synuclein mutant proteins (with a point mutation, A53T, and a C-terminal 20 amino acid truncation) in the eukaryotic model Dictyostelium discoideum. Mitochondrial disease has been well studied in D. discoideum and, unlike in mammals, mitochondrial dysfunction results in a clear set of defective phenotypes. These defective phenotypes are caused by the chronic hyperactivation of the cellular energy sensor, AMP-activated protein kinase (AMPK). Expression of α-synuclein wild type and mutant forms was toxic to the cells and mitochondrial function was dysregulated. Some but not all of the defective phenotypes could be rescued by down regulation of AMPK revealing both AMPK-dependent and -independent mechanisms. Importantly, we also show that the C-terminus of α-synuclein is required and sufficient for the localisation of the protein to the cell cortex in D. discoideum. Full article
(This article belongs to the Special Issue Nonmammalian Models for Neurodegenerative and Neurological Disorders)
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Review

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31 pages, 691 KiB  
Review
Dictyostelium discoideum: A Model System for Neurological Disorders
by Claire Louise Storey, Robin Simon Brooke Williams, Paul Robert Fisher and Sarah Jane Annesley
Cells 2022, 11(3), 463; https://doi.org/10.3390/cells11030463 - 28 Jan 2022
Cited by 6 | Viewed by 3778
Abstract
Background: The incidence of neurological disorders is increasing due to population growth and extended life expectancy. Despite advances in the understanding of these disorders, curative strategies for treatment have not yet eventuated. In part, this is due to the complexities of the disorders [...] Read more.
Background: The incidence of neurological disorders is increasing due to population growth and extended life expectancy. Despite advances in the understanding of these disorders, curative strategies for treatment have not yet eventuated. In part, this is due to the complexities of the disorders and a lack of identification of their specific underlying pathologies. Dictyostelium discoideum has provided a useful, simple model to aid in unraveling the complex pathological characteristics of neurological disorders including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, neuronal ceroid lipofuscinoses and lissencephaly. In addition, D. discoideum has proven to be an innovative model for pharmaceutical research in the neurological field. Scope of review: This review describes the contributions of D. discoideum in the field of neurological research. The continued exploration of proteins implicated in neurological disorders in D. discoideum may elucidate their pathological roles and fast-track curative therapeutics. Full article
(This article belongs to the Special Issue Nonmammalian Models for Neurodegenerative and Neurological Disorders)
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