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Special Issue "Drosophila Models for Neurodegenerative Diseases: Achievements and Prospects"

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: 31 July 2022.

Special Issue Editors

Dr. Serge Birman
E-Mail Website
Guest Editor
Brain Plasticity Unit, CNRS, ESPCI Paris, PSL Research University, Paris, France
Interests: neurotransmission; behavior; neurological disorders
Dr. Emi Nagoshi
E-Mail Website
Guest Editor
Department of Genetics and Evolution, University of Geneva, Geneva, Switzerland
Interests: circadian rhythms; sleep; neurodegeneration
Dr. Frank Hirth
E-Mail Website
Guest Editor
King’s College London; Institute of Psychiatry, Psychology and Neuroscience, London, UK; Maurice Wohl Clinical Neuroscience Institute
Interests: brain development and evolution; neuroscience; mental health disorders

Special Issue Information

Dear Colleagues,

Neurodegenerative diseases affect an ever-increasing aging population. The disorders range from motor dysfunction to psychiatric troubles and dementia. So far, no cure is available, but steady progress is being made. Part of this progress is due to studies in the fruit fly Drosophila which have led to major insights into the cellular and molecular mechanisms underlying neurodegeneration.

More than 20 years after the first reports describing neurodegeneration in flies, this IJMS Special Issue aims to summarize what Drosophila studies have contributed to the understanding and treatment of neurodegeneration and what prospects fly models can offer in the future. Given that cures are still unavailable, progress in this field requires a deeper knowledge of the mechanisms underlying brain development, homeostasis, and maintenance, as well as the function of genes, whose mutations are associated with neurodegenerative disorders. This is where recent progress in Drosophila neurodegeneration research could definitively help, as evidenced by various experts in the field whose contribution will be collected in this Special Issue.

Here, we aim to shed light on the benefits of using Drosophila to complement, or even overcome the limitations of studies carried out in humans and other animal models. The advantages of Drosophila are primarily the ease with which it is possible to perform in vivo studies that cover all aspects of the diseases from genes to circuits and behavior; the well-described anatomy and cellular organization of its brain, which is now close to being completely described at the level of neural circuits and synaptic connections; and the dazzling variety of genetic tools that are continuously developed and improved to study gene functions and neuronal activity in situ at cell and circuit resolution.

These ongoing methodological refinements promise to enable us to elucidate every step of the pathogenic processes underlying neurodegeneration, with the ultimate goal to uncover the original causative failures and to test novel targets and treatments to stop or even reverse the progression of these devastating illnesses.

Dr. Serge Birman
Dr. Emi Nagoshi
Dr. Frank Hirth
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neurodegeneration
  • Drosophila
  • Alzheimer’s disease
  • Parkinson’s disease
  • motor neuron disease
  • Huntington’s disease
  • dementia
  • repeat expansion disease
  • α-synuclein
  • amyloid beta
  • Tau
  • TDP-43

Published Papers (6 papers)

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Research

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Article
Glitazone Treatment Rescues Phenotypic Deficits in a Fly Model of Gaucher/Parkinson’s Disease
Int. J. Mol. Sci. 2021, 22(23), 12740; https://doi.org/10.3390/ijms222312740 - 25 Nov 2021
Viewed by 207
Abstract
Parkinson’s Disease (PD) is the most common movement disorder, and the strongest genetic risk factor for PD is mutations in the glucocerebrosidase gene (GBA). Mutations in GBA also lead to the development of Gaucher Disease (GD), the most common type of [...] Read more.
Parkinson’s Disease (PD) is the most common movement disorder, and the strongest genetic risk factor for PD is mutations in the glucocerebrosidase gene (GBA). Mutations in GBA also lead to the development of Gaucher Disease (GD), the most common type of lysosomal storage disorder. Current therapeutic approaches fail to address neurological GD symptoms. Therefore, identifying therapeutic strategies that improve the phenotypic traits associated with GD/PD in animal models may provide an opportunity for treating neurological manifestations of GD/PD. Thiazolidinediones (TZDs, also called glitazones) are a class of compounds targeted for the treatment of type 2 diabetes, and have also shown promise for the treatment of neurodegenerative disease, including PD. Here, we tested the efficacy of glitazone administration during development in a fly GD model with deletions in the GBA homolog, dGBA1b (GBA1ΔTT/ΔTT). We observed an optimal dose of pioglitazone (PGZ) at a concentration of 1 μM that reduced sleep deficits, locomotor impairments, climbing defects, and restoration of normal protein levels of Ref(2)P, a marker of autophagic flux, in GBA1ΔTT/ΔTT mutant flies, compared to GBA1+/+ control flies. These data suggest that PGZ may represent a potential compound with which to treat GD/PD by improving function of lysosomal-autophagy pathways, a cellular process that removes misfolded or aggregated proteins. Full article
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Article
Chronic Exposure to Paraquat Induces Alpha-Synuclein Pathogenic Modifications in Drosophila
Int. J. Mol. Sci. 2021, 22(21), 11613; https://doi.org/10.3390/ijms222111613 - 27 Oct 2021
Viewed by 425
Abstract
Parkinson’s disease (PD) is characterized by the progressive accumulation of neuronal intracellular aggregates largely composed of alpha-Synuclein (αSyn) protein. The process of αSyn aggregation is induced during aging and enhanced by environmental stresses, such as the exposure to pesticides. Paraquat (PQ) is an [...] Read more.
Parkinson’s disease (PD) is characterized by the progressive accumulation of neuronal intracellular aggregates largely composed of alpha-Synuclein (αSyn) protein. The process of αSyn aggregation is induced during aging and enhanced by environmental stresses, such as the exposure to pesticides. Paraquat (PQ) is an herbicide which has been widely used in agriculture and associated with PD. PQ is known to cause an increased oxidative stress in exposed individuals but the consequences of such stress on αSyn conformation remains poorly understood. To study αSyn pathogenic modifications in response to PQ, we exposed Drosophila expressing human αSyn to a chronic PQ protocol. We first showed that PQ exposure and αSyn expression synergistically induced fly mortality. The exposure to PQ was also associated with increased levels of total and phosphorylated forms of αSyn in the Drosophila brain. Interestingly, PQ increased the detection of soluble αSyn in highly denaturating buffer but did not increase αSyn resistance to proteinase K digestion. These results suggest that PQ induces the accumulation of toxic soluble and misfolded forms of αSyn but that these toxic forms do not form fibrils or aggregates that are detected by the proteinase K assay. Collectively, our results demonstrate that Drosophila can be used to study the effect of PQ or other environmental neurotoxins on αSyn driven pathology. Full article
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Article
Loss of swiss cheese in Neurons Contributes to Neurodegeneration with Mitochondria Abnormalities, Reactive Oxygen Species Acceleration and Accumulation of Lipid Droplets in Drosophila Brain
Int. J. Mol. Sci. 2021, 22(15), 8275; https://doi.org/10.3390/ijms22158275 - 31 Jul 2021
Viewed by 1143
Abstract
Various neurodegenerative disorders are associated with human NTE/PNPLA6 dysfunction. Mechanisms of neuropathogenesis in these diseases are far from clearly elucidated. Hereditary spastic paraplegia belongs to a type of neurodegeneration associated with NTE/PNLPLA6 and is implicated in neuron death. In this study, we used [...] Read more.
Various neurodegenerative disorders are associated with human NTE/PNPLA6 dysfunction. Mechanisms of neuropathogenesis in these diseases are far from clearly elucidated. Hereditary spastic paraplegia belongs to a type of neurodegeneration associated with NTE/PNLPLA6 and is implicated in neuron death. In this study, we used Drosophila melanogaster to investigate the consequences of neuronal knockdown of swiss cheese (sws)—the evolutionarily conserved ortholog of human NTE/PNPLA6—in vivo. Adult flies with the knockdown show longevity decline, locomotor and memory deficits, severe neurodegeneration progression in the brain, reactive oxygen species level acceleration, mitochondria abnormalities and lipid droplet accumulation. Our results suggest that SWS/NTE/PNPLA6 dysfunction in neurons induces oxidative stress and lipid metabolism alterations, involving mitochondria dynamics and lipid droplet turnover in neurodegeneration pathogenesis. We propose that there is a complex mechanism in neurological diseases such as hereditary spastic paraplegia, which includes a stress reaction, engaging mitochondria, lipid droplets and endoplasmic reticulum interplay. Full article
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Article
Genetic Screen in Adult Drosophila Reveals That dCBP Depletion in Glial Cells Mitigates Huntington Disease Pathology through a Foxo-Dependent Pathway
Int. J. Mol. Sci. 2021, 22(8), 3884; https://doi.org/10.3390/ijms22083884 - 09 Apr 2021
Cited by 1 | Viewed by 641
Abstract
Huntington’s disease (HD) is a progressive and fatal autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in the first exon of the huntingtin gene (HTT). In spite of considerable efforts, there is currently no treatment to stop or delay [...] Read more.
Huntington’s disease (HD) is a progressive and fatal autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in the first exon of the huntingtin gene (HTT). In spite of considerable efforts, there is currently no treatment to stop or delay the disease. Although HTT is expressed ubiquitously, most of our knowledge has been obtained on neurons. More recently, the impact of mutant huntingtin (mHTT) on other cell types, including glial cells, has received growing interest. It is currently unclear whether new pathological pathways could be identified in these cells compared to neurons. To address this question, we performed an in vivo screen for modifiers of mutant huntingtin (HTT-548-128Q) induced pathology in Drosophila adult glial cells and identified several putative therapeutic targets. Among them, we discovered that partial nej/dCBP depletion in these cells was protective, as revealed by strongly increased lifespan and restored locomotor activity. Thus, dCBP promotes the HD pathology in glial cells, in contrast to previous opposite findings in neurons. Further investigations implicated the transcriptional activator Foxo as a critical downstream player in this glial protective pathway. Our data suggest that combinatorial approaches combined to specific tissue targeting may be required to uncover efficient therapies in HD. Full article
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Review

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Review
Exploring Aβ Proteotoxicity and Therapeutic Candidates Using Drosophila melanogaster
Int. J. Mol. Sci. 2021, 22(19), 10448; https://doi.org/10.3390/ijms221910448 - 28 Sep 2021
Viewed by 441
Abstract
Alzheimer’s disease is a widespread and devastating neurological disorder associated with proteotoxic events caused by the misfolding and aggregation of the amyloid-β peptide. To find therapeutic strategies to combat this disease, Drosophila melanogaster has proved to be an excellent model organism that is [...] Read more.
Alzheimer’s disease is a widespread and devastating neurological disorder associated with proteotoxic events caused by the misfolding and aggregation of the amyloid-β peptide. To find therapeutic strategies to combat this disease, Drosophila melanogaster has proved to be an excellent model organism that is able to uncover anti-proteotoxic candidates due to its outstanding genetic toolbox and resemblance to human disease genes. In this review, we highlight the use of Drosophila melanogaster to both study the proteotoxicity of the amyloid-β peptide and to screen for drug candidates. Expanding the knowledge of how the etiology of Alzheimer’s disease is related to proteotoxicity and how drugs can be used to block disease progression will hopefully shed further light on the field in the search for disease-modifying treatments. Full article
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Review
Nutraceutical and Probiotic Approaches to Examine Molecular Interactions of the Amyloid Precursor Protein APP in Drosophila Models of Alzheimer’s Disease
Int. J. Mol. Sci. 2021, 22(13), 7022; https://doi.org/10.3390/ijms22137022 - 29 Jun 2021
Viewed by 1121
Abstract
Studies using animal models have shed light into the molecular and cellular basis for the neuropathology observed in patients with Alzheimer’s disease (AD). In particular, the role of the amyloid precursor protein (APP) plays a crucial role in the formation of senile plaques [...] Read more.
Studies using animal models have shed light into the molecular and cellular basis for the neuropathology observed in patients with Alzheimer’s disease (AD). In particular, the role of the amyloid precursor protein (APP) plays a crucial role in the formation of senile plaques and aging-dependent degeneration. Here, we focus our review on recent findings using the Drosophila AD model to expand our understanding of APP molecular function and interactions, including insights gained from the fly homolog APP-like (APPL). Finally, as there is still no cure for AD, we review some approaches that have shown promising results in ameliorating AD-associated phenotypes, with special attention on the use of nutraceuticals and their molecular effects, as well as interactions with the gut microbiome. Overall, the phenomena described here are of fundamental significance for understanding network development and degeneration. Given the highly conserved nature of fundamental signaling pathways, the insight gained from animal models such as Drosophila melanogaster will likely advance the understanding of the mammalian brain, and thus be relevant to human health. Full article
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