Drosophila studies help in characterization of disease-associated variants in ATAD3A

Genome Med. 2021 Apr 12;13(1):55. doi: 10.1186/s13073-021-00873-3.

Functional interpretation of ATAD3A variants in neuro-mitochondrial phenotypes.

Yap ZY, Park YH, Wortmann SB, Gunning AC, Ezer S, Lee S, Duraine L, Wilichowski E, Wilson K, Mayr JA, Wagner M, Li H, Kini U, Black ED, Monaghan KG, Lupski JR, Ellard S, Westphal DS, Harel T, Yoon WH

From the abstract:

ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane-anchored protein involved in diverse processes including mitochondrial dynamics, mitochondrial DNA organization, and cholesterol metabolism. Biallelic deletions (null), recessive missense variants (hypomorph), and heterozygous missense variants or duplications (antimorph) in
ATAD3A lead to neurological syndromes in humans. ... To expand the mutational spectrum of ATAD3A variants and to provide functional interpretation of missense alleles in trans to deletion alleles, we
performed exome sequencing ... in ATAD3A in individuals with neurological and mitochondrial phenotypes. A Drosophila Atad3a Gal4 knockin-null allele was generated using CRISPR-Cas9 genome editing technology to aid the interpretation of variants. ... We report 13 individuals from 8 unrelated families with biallelic ATAD3A variants. ... Affected individuals exhibited findings previously associated with ATAD3A pathogenic variation ... Drosophila studies indicated that Phe50Leu, Gly236Val, Arg327Pro, and Lys568del are severe loss-of-function alleles ... Leu77Val and Arg170Trp
are partial loss-of-function alleles that cause progressive locomotion defects ... Our findings expand the allelic spectrum of ATAD3A variants and exemplify the use of a functional assay in Drosophila to aid variant interpretation.

DOI: 10.1186/s13073-021-00873-3
PMID: 33845882

Two models and the 'two-hit' model: Study in flies and Xenopus related to neurodevelopmental disorders

PLoS Genet. 2021 Apr 5;17(4):e1009112. doi: 10.1371/journal.pgen.1009112.

Functional assessment of the "two-hit" model for neurodevelopmental defects in Drosophila and X. laevis.

Pizzo L, Lasser M, Yusuff T, Jensen M, Ingraham P, Huber E, Singh MD, Monahan C, Iyer J, Desai I, Karthikeyan S, Gould DJ, Yennawar S, Weiner AT, Pounraja VK, Krishnan A, Rolls MM, Lowery LA, Girirajan S

Abstract:

We previously identified a deletion on chromosome 16p12.1 that is mostly inherited and associated with multiple neurodevelopmental outcomes, where severely affected probands carried an excess of rare pathogenic variants compared to mildly affected carrier parents. We hypothesized that the 16p12.1 deletion sensitizes the genome for disease, while "second-hits" in the genetic background modulate the phenotypic trajectory. To test this model, we examined how neurodevelopmental defects conferred by knockdown of individual 16p12.1 homologs are modulated by simultaneous knockdown of homologs of "second-hit" genes in Drosophila melanogaster and Xenopus laevis. We observed that knockdown of 16p12.1 homologs affect multiple phenotypic domains, leading to delayed developmental timing, seizure susceptibility, brain alterations, abnormal dendrite and axonal morphology, and cellular proliferation defects. Compared to genes within the 16p11.2 deletion, which has higher de novo occurrence, 16p12.1  homologs were less likely to interact with each other in Drosophila models or a human brain-specific interaction network, suggesting that interactions with "second-hit" genes may confer higher impact towards neurodevelopmental phenotypes. Assessment of 212 pairwise interactions in Drosophila between
16p12.1 homologs and 76 homologs of patient-specific "second-hit" genes (such as ARID1B and CACNA1A), genes within neurodevelopmental pathways (such as PTEN and UBE3A), and transcriptomic targets (such as DSCAM and TRRAP) identified genetic interactions in 63% of the tested pairs. In 11 out of 15 families, patient-specific "second-hits" enhanced or suppressed the phenotypic effects of one or many 16p12.1 homologs in 32/96 pairwise combinations tested. In fact, homologs of SETD5 synergistically interacted with homologs of MOSMO in both Drosophila and X. laevis, leading to modified cellular and brain phenotypes, as well as axon outgrowth defects that were not observed with knockdown of either individual homolog. Our results suggest that several 16p12.1 genes sensitize the  genome towards neurodevelopmental defects, and complex interactions with "second-hit" genes determine the ultimate phenotypic manifestation.

DOI: 10.1371/journal.pgen.1009112
PMID: 33819264

Review: Drosophila models of neurological diseases including ALS, CMT and Sotos syndrome

Exp Cell Res. 2021 Mar 31:112584. doi: 10.1016/j.yexcr.2021.112584. Online ahead
of print.

Drosophila models to study causative genes for human rare intractable
neurological diseases

Yamaguchi M, Lee IS, Jantrapirom S, Suda K, Yoshida H

Abstract

Drosophila is emerging as a convenient model for investigating human diseases. Functional homologues of almost 75% of human disease-related genes are found in Drosophila. Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease that causes defects in motoneurons. Charcot-Marie-Tooth disease (CMT) is one of the most commonly found inherited neuropathies affecting both motor and  sensory neurons. No effective therapy has been established for either of these diseases. In this review, after overviewing ALS, Drosophila models targeting several ALS-causing genes, including TDP-43, FUS and Ubiquilin2, are described with their genetic interactants. Then, after overviewing CMT, examples of
Drosophila models targeting several CMT-causing genes, including mitochondria-related genes and FIG 4, are also described with their genetic interactants. In addition, we introduce Sotos syndrome caused by mutations in the epigenetic regulator gene NSD1. Lastly, several genes and pathways that commonly interact with ALS- and/or CMT-causing genes are described. In the case of ALS and CMT that have many causative genes, it may be not practical to perform gene therapy for each of the many disease-causing genes. The possible uses of the common genes and pathways as novel diagnosis markers and effective  therapeutic targets are discussed.

Copyright © 2021. Published by Elsevier Inc.

DOI: 10.1016/j.yexcr.2021.112584
PMID: 33812867

Building bridges--new ModelMatcher resource

Readers of this blog are likely be interested to read this article appearing in Lab Animal and check out the new ModelMatcher online resource featured in the article. ModelMatcher was recently launched by Yamamoto and colleagues at Baylor College of Medicine. 

Are you a clinician interested to partner with labs that can harness the power of genetic model systems? Or an expert in Drosophila, C. elegans, or other models interested to partner with clinicians? 

Click to learn more! 

Lab Animal, "Model matchmaking" by Ellen P. Neff
ModelMatcher online resource

Additional resources of interest include:
DIOPT for ortholog mapping
MARRVEL for human disease variant exploration
BioLitMine for gene-centric literature search
Matchmaker Exchange
Monarch Initiative Explorer

Review article: "Investigating rare and ultrarare epilepsy syndromes with Drosophila models"

Fac Rev. 2021 Jan 29;10:10. doi: 10.12703/r/10-10. eCollection 2021.

Investigating rare and ultrarare epilepsy syndromes with Drosophila models.

Lasko P(1)(2), Lüthy K(1)(3).

Author information:
(1)Department of Human Genetics, Radboud University Medical Centre, Nijmegen,
Netherlands.
(2)Department of Biology, McGill University, Montréal, Québec, Canada.
(3)Donders Institute for Brain, Cognition and Behaviour, Radboud University
Medical Centre, Nijmegen, Netherlands.

Abstract:

One in three epilepsy cases is drug resistant, and seizures often begin in  infancy, when they are life-threatening and when therapeutic options are highly limited. An important tool for prioritizing and validating genes associated with epileptic conditions, which is suitable for large-scale screening, is disease  modeling in Drosophila. Approximately two-thirds of disease genes are conserved in Drosophila, and gene-specific fly models exhibit behavioral changes that are  related to symptoms of epilepsy. Models are based on behavior readouts, seizure-like attacks and paralysis following stimulation, and neuronal,  cell-biological readouts that are in the majority based on changes in nerve cell activity or morphology. In this review, we focus on behavioral phenotypes. Importantly, Drosophila modeling is independent of, and complementary to, other approaches that are computational and based on systems analysis. The large  number of known epilepsy-associated gene variants indicates a need for efficient research strategies. We will discuss the status quo of epilepsy disease modelling in Drosophila and describe promising steps towards the development of new drugs to reduce seizure rates and alleviate other epileptic symptoms.

Copyright: © 2021 Lasko P et al.

DOI: 10.12703/r/10-10
PMCID: PMC7894260
PMID: 33659928

Drosophila research helps inform hypothesis regarding effects of macrophages on metabolism

Front Cell Dev Biol. 2021 Feb 15;9:629238. doi: 10.3389/fcell.2021.629238.
eCollection 2021.

Polarization of Macrophages in Insects: Opening Gates for Immuno-Metabolic
Research.

Bajgar A(1), Krejčová G(1), Doležal T(1).

Author information:
(1)Department of Molecular Biology and Genetics, University of South Bohemia,
Ceske Budejovice, Czechia.

From the abstract:

Insulin resistance and cachexia represent severe metabolic syndromes accompanying a variety of human pathological states, from life-threatening cancer and sepsis to chronic inflammatory states, such as obesity and autoimmune disorders. ... Current progress in insect immuno-metabolic research reveals that the induction of insulin resistance might represent an adaptive mechanism during the acute phase of bacterial infection. In Drosophila, insulin resistance is induced by signaling factors released by bactericidal macrophages as a reflection of their metabolic polarization toward aerobic glycolysis. Such metabolic adaptation enables them to combat the invading pathogens efficiently but also makes them highly nutritionally demanding. Therefore, systemic metabolism has to be adjusted upon macrophage activation ... We hypothesize that insulin resistance evoked by macrophage-derived signaling factors represents an adaptive mechanism for the mobilization of sources and their preferential delivery toward the activated immune system. We consider here the validity of the presented model for mammals and human medicine. ... Chronic insulin resistance is at the base of many human metabolically conditioned diseases such as non-alcoholic steatohepatitis, atherosclerosis, diabetes, and cachexia. Therefore, revealing the original biological relevance of cytokine-induced insulin resistance may help to develop a suitable strategy for treating these frequent diseases.

Copyright © 2021 Bajgar, Krejčová and Doležal.

DOI: 10.3389/fcell.2021.629238
PMCID: PMC7917182
PMID: 33659253

It takes a zoo: Use of Drosophila and other organisms in aging research (review article)

Cell Mol Life Sci. 2021 Feb;78(4):1275-1304. doi: 10.1007/s00018-020-03658-w.
Epub 2020 Oct 9.

Nontraditional systems in aging research: an update.

Mikuła-Pietrasik J(1), Pakuła M(2), Markowska M(2), Uruski P(2),
Szczepaniak-Chicheł L(2), Tykarski A(2), Książek K(3).

Author information:
(1)Department of Pathophysiology of Ageing and Civilization Diseases, Poznań
University of Medical Sciences, Długa 1/2 Str., 61-848, Poznań, Poland.
(2)Department of Hypertensiology, Poznań University of Medical Sciences, Długa
1/2 Str., 61-848, Poznań, Poland.
(3)Department of Pathophysiology of Ageing and Civilization Diseases, Poznań
University of Medical Sciences, Długa 1/2 Str., 61-848, Poznań, Poland.
kksiazek@ump.edu.pl.

Research on the evolutionary and mechanistic aspects of aging and longevity has  a reductionist nature, as the majority of knowledge originates from experiments on a relatively small number of systems and species. Good examples are the studies on the cellular, molecular, and genetic attributes of aging (senescence) that are primarily based on a narrow group of somatic cells, especially fibroblasts. Research on aging and/or longevity at the organismal level is dominated, in turn, by experiments on Drosophila melanogaster, worms (Caenorhabditis elegans), yeast (Saccharomyces cerevisiae), and higher organisms
such as mice and humans. Other systems of aging, though numerous, constitute the minority. In this review, we collected and discussed a plethora of up-to-date findings about studies of aging, longevity, and sometimes even immortality in several valuable but less frequently used systems, including bacteria (Caulobacter crescentus, Escherichia coli), invertebrates (Turritopsis dohrnii, Hydra sp., Arctica islandica), fishes (Nothobranchius sp., Greenland shark), reptiles (giant tortoise), mammals (blind mole rats, naked mole rats, bats, elephants, killer whale), and even 3D organoids, to prove that they offer biogerontologists as much as the more conventional tools. At the same time, the diversified knowledge gained owing to research on those species may help to reconsider aging from a broader perspective, which should translate into a better understanding of this tremendously complex and clearly system-specific  phenomenon.

DOI: 10.1007/s00018-020-03658-w
PMID: 33034696