Fly eye assay explored as a tool for assessing potential therapeutic treatments of chronic myeloid leukemia

Haematologica. 2020 Jan 31;105(2):387-397. doi: 10.3324/haematol.2019.219394. Print 2020.

Validation of a Drosophila model of wild-type and T315I mutated BCR-ABL1 in chronic myeloid leukemia: an effective platform for treatment screening.

Outa AA, Abubaker D, Bazarbachi A, Sabban ME, Shirinian M, Nasr R

Abstract:

Chronic myeloid leukemia is caused by a balanced chromosomal translocation resulting in the formation of BCR-ABL1 fusion gene encoding a constitutively active BCR-ABL1 tyrosine kinase, which activates multiple signal transduction pathways leading to malignant transformation. Standard treatment of chronic myeloid leukemia is based on tyrosine kinase inhibitors; however, some mutations have proven elusive particularly the T315I mutation. Drosophila melanogaster is an established in vivo model for human diseases including cancer. The targeted expression of chimeric human/fly and full human BCR-ABL1 in Drosophila eyes has been shown to result in detrimental effects. In this study, we expressed human BCR-ABL1p210 and the resistant BCR-ABL1p210/T315I fusion oncogenes in Drosophila eyes. Expression of BCR-ABL1p210/T315I resulted in a severe distortion of the ommatidial architecture of adult eyes with a more prominent rough eye phenotype compared to milder phenotypes in BCR-ABL1p210 reflecting a stronger oncogenic potential of the mutant. We then assessed the efficacy of the currently used tyrosine kinase inhibitors in BCR-ABL1p210 and BCR-ABL1p210/T315I expressing flies. Treatment of BCR-ABL1p210 expressing flies with potent kinase inhibitors (dasatinib and ponatinib) resulted in the rescue of ommatidial loss and the restoration of normal development. Taken together, we provide a chronic myeloid leukemia tailored BCR-ABL1p210 and BCR-ABL1p210/T315I fly model which can be used to test new compounds with improved therapeutic indices.

DOI: 10.3324/haematol.2019.219394
PMCID: PMC7012492
PMID: 31101753

Study exploring impact of phophorylation state of PINK1 includes rescue of PINK1 definiciency in Drosophila as investigative tool (relevance to Parkinsons Disease)

EMBO Rep. 2020 Aug 5;21(8):e48686. doi: 10.15252/embr.201948686. Epub 2020 Jun 2.

PINK1 phosphorylates Drp1(S616) to regulate mitophagy-independent mitochondrial dynamics.

Han H, Tan J, Wang R, Wan H, He Y, Yan X, Guo J, Gao Q, Li J, Shang S, Chen F, Tian R, Liu W,
Liao L, Tang B, Zhang Z

Abstract:

Impairment of PINK1/parkin-mediated mitophagy is currently proposed to be the molecular basis of mitochondrial abnormality in Parkinson's disease (PD). We here demonstrate that PINK1 directly phosphorylates Drp1 on S616. Drp1S616 phosphorylation is significantly reduced in cells and mouse tissues deficient for PINK1, but unaffected by parkin inactivation. PINK1-mediated mitochondrial fission is Drp1S616 phosphorylation dependent. Overexpression of either wild-type Drp1 or of the phosphomimetic mutant Drp1S616D, but not a dephosphorylation-mimic mutant Drp1S616A, rescues PINK1 deficiency-associated phenotypes in Drosophila. Moreover, Drp1 restores PINK1-dependent mitochondrial fission in ATG5-null cells and ATG7-null Drosophila. Reduced Drp1S616 phosphorylation is detected in fibroblasts derived from 4 PD patients harboring PINK1 mutations and in 4 out of 7 sporadic PD cases. Taken together, we have identified Drp1 as a substrate of PINK1 and a novel mechanism how PINK1 regulates mitochondrial fission independent of parkin and autophagy. Our results further link impaired PINK1-mediated Drp1S616 phosphorylation with the pathogenesis of both familial and sporadic PD.

DOI: 10.15252/embr.201948686
PMCID: PMC7403662
PMID: 32484300

Report relevant to age-related disorders tests effects of treatment with alpha-lipoic acid on Drosophila

EMBO Rep. 2020 Aug 5;21(8):e49583. doi: 10.15252/embr.201949583. Epub 2020 Jul 9.

Lipoic acid rejuvenates aged intestinal stem cells by preventing age-associated endosome reduction.

Du G, Qiao Y, Zhuo Z, Zhou J, Li X, Liu Z, Li Y, Chen H

Comment in
EMBO Rep. 2020 Aug 5;21(8):e51175.

Abstract:

The age-associated decline of adult stem cell function is closely related to the decline in tissue function and age-related diseases. However, the underlying mechanisms that ultimately lead to the observed functional decline of stem cells still remain largely unexplored. This study investigated Drosophila midguts and found a continuous downregulation of lipoic acid synthase, which encodes the key enzyme for the endogenous synthesis of alpha-lipoic acid (ALA), upon aging. Importantly, orally administration of ALA significantly reversed the age-associated hyperproliferation of intestinal stem cells (ISCs) and the
observed decline of intestinal function, thus extending the lifespan of Drosophila. This study reports that ALA reverses age-associated ISC dysfunction by promoting the activation of the endocytosis-autophagy network, which decreases in aged ISCs. Moreover, this study suggests that ALA may be used as a safe and effective anti-aging compound for the treatment of ISC-dysfunction-related diseases and for the promotion of healthy aging in humans.

DOI: 10.15252/embr.201949583
PMCID: PMC7403706
PMID: 32648369

Reports related to neurodegenerative diseases use Drosophila as a test system

Aging Cell. 2021 Apr 28:e13365. doi: 10.1111/acel.13365. Online ahead of print.

Vesicular glutamate transporter modulates sex differences in dopamine neuron
vulnerability to age-related neurodegeneration.

Buck SA, Steinkellner T, Aslanoglou D, Villeneuve M, Bhatte SH, Childers VC), Rubin SA, De Miranda BR, O'Leary EI, Neureiter EG, Fogle KJ, Palladino MJ, Logan RW, Glausier JR, Fish KN, Lewis DA(2), Greenamyre JT, McCabe BD, Cheetham CEJ, Hnasko TS, Freyberg Z

Age is the greatest risk factor for Parkinson's disease (PD) which causes progressive loss of dopamine (DA) neurons, with males at greater risk than females. Intriguingly, some DA neurons are more resilient to degeneration than others. Increasing evidence suggests that vesicular glutamate transporter (VGLUT) expression in DA neurons plays a role in this selective vulnerability. We investigated the role of DA neuron VGLUT in sex- and age-related differences in DA neuron vulnerability using the genetically tractable Drosophila model. We found sex differences in age-related DA neurodegeneration and its associated locomotor behavior, where males exhibit significantly greater decreases in both DA neuron number and locomotion during aging compared with females. We discovered that dynamic changes in DA neuron VGLUT expression mediate these age- and sex-related differences, as a potential compensatory mechanism for diminished DA neurotransmission during aging. Importantly, female Drosophila possess higher levels of VGLUT expression in DA neurons compared with males, and this finding is conserved across flies, rodents, and humans. Moreover, we showed that diminishing VGLUT expression in DA neurons eliminates females' greater resilience to DA neuron loss across aging. This offers a new mechanism for sex differences in selective DA neuron vulnerability to age-related DA neurodegeneration. Finally, in mice, we showed that the ability of DA neurons to achieve optimal control over VGLUT expression is essential for DA neuron survival. These findings lay the groundwork for the manipulation of DA neuron VGLUT expression as a novel therapeutic strategy to boost DA neuron resilience to age- and PD-related neurodegeneration.

DOI: 10.1111/acel.13365
PMID: 33909313

 

Cell Death Dis. 2020 Sep 10;11(9):739. doi: 10.1038/s41419-020-02942-8.

Enhanced accumulation of reduced glutathione by Scopoletin improves
survivability of dopaminergic neurons in Parkinson's model.

Pradhan P, Majhi O, Biswas A, Joshi VK, Sinha D

Parkinson's disease (PD) is a neuromotor disorder, primarily manifested by motor anomalies due to progressive loss of dopaminergic neurons. Although alterations in genetic factors have been linked with its etiology, exponential accumulation of environmental entities such as reactive oxygen species (ROS) initiate a cyclic chain reaction resulting in accumulation of cellular inclusions, dysfunctional mitochondria, and overwhelming of antioxidant machinery, thus accelerating disease pathogenesis. Involvement of oxidative stress in PD is further substantiated through ROS induced Parkinsonian models and elevated oxidative markers in clinical PD samples; thereby, making modulation of neuronal oxidative load as one of the major approaches in management of PD. Here we have found a potent antioxidant moiety Scopoletin (Sp), a common derivative in most of the nootropic herbs, with robust neuroprotective ability. Sp increased cellular resistance to ROS through efficient recycling of GSH to prevent oxidative damage. The Sp treated cells showed higher loads of reduced glutathione making them resistant to perturbation of antioxidant machinery or neurotoxin MPP+. Sp could restore the redox balance, mitochondrial function, and prevented oxidative damage, leading to recovery of dopaminergic neural networks and motion abilities in Drosophila genetic model of PD. Our data also suggest that Sp, in combination increases the therapeutic potency of L-DOPA by mitigating its chronic toxicity. Together, we highlight the possible ability of Sp in preventing oxidative stress mediated loss of dopaminergic neurons and at the same time enhance the efficacy of dopamine recharging regimens.

DOI: 10.1038/s41419-020-02942-8
PMCID: PMC7484898
PMID: 32913179

Drosophila used in study associating variants in UNC13B with epilepsy and/or febrile seizures

Brain. 2021 Apr 20:awab164. doi: 10.1093/brain/awab164. Online ahead of print.

UNC13B variants associated with partial epilepsy with favourable outcome.

Wang J(, Qiao JD, Liu XR, Liu DT, Chen YH, Wu Y, Sun Y, Yu J, Ren RN, Mei Z, Liu YX, Shi YW, Jiang M, Lin SM, He N, Li B, Bian WJ, Li BM(, Yi YH, Su T, Liu HK, Gu WY, Liao WP; China Epilepsy Gene 1.0 Project.

From the abstract:

"The unc-13 homolog B (UNC13B) gene encodes a presynaptic protein ... In this study we screened for novel genetic variants in a cohort of 446 unrelated cases (families) with partial epilepsy ... UNC13B variants were identified in 12 individuals affected by partial epilepsy and/or febrile seizures from eight unrelated families. ... The identified UNC13B variants included one nonsense variant, two variants at or around a splice site, one compound heterozygous missense variant, and four missense variants that cosegregated in the families. The frequency of UNC13B variants identified in the present study was significantly higher than that in a control cohort of Han Chinese and controls of the East Asian and all populations in the Genome Aggregation Database. Computational modeling, including hydrogen bond and docking analyses, suggested that the variants lead to functional impairment. In Drosophila, seizure rate and duration were increased by Unc13b knockdown compared to wild-type flies, but these effects were less pronounced than in sodium voltage-gated channel alpha subunit 1 (Scn1a) knockdown Drosophila. Electrophysiologic recordings showed that excitatory neurons in Unc13b-deficient flies exhibited increased excitability. These results suggest that UNC13B is potentially associated with epilepsy. ..."

DOI: 10.1093/brain/awab164
PMID: 33876820

Cross-species analysis related to Huntington's disease (fly, mouse, human)

Elife. 2021 Apr 19;10:e64564. doi: 10.7554/eLife.64564. Online ahead of print.

Downregulation of glial genes involved in synaptic function mitigates Huntington's Disease pathogenesis.

Onur TS, Laitman A, Zhao H, Keyho R, Kim H, Wang J, Mair M, Wang H, Li L, Perez A, de Haro M, Wan YW, Allen G, Lu B, Al-Ramahi I, Liu Z, Botas J

Abstract:

Most research on neurodegenerative diseases has focused on neurons, yet glia help form and maintain the synapses whose loss is so prominent in these conditions. To investigate the contributions of glia to Huntington's disease (HD), we profiled the gene expression alterations of Drosophila expressing human mutant Huntingtin (mHTT) in either glia or neurons and compared these changes to what is observed in HD human and HD mice striata. A large portion of conserved genes are concordantly dysregulated across the three species; we tested these genes in a high-throughput behavioral assay and found that downregulation of genes involved in synapse assembly mitigated pathogenesis and behavioral deficits. To our surprise, reducing dNRXN3 function in glia was sufficient to improve the phenotype of flies expressing mHTT in neurons, suggesting that mHTT's toxic effects in glia ramify throughout the brain. This supports a model in which dampening synaptic function is protective because it attenuates the  excitotoxicity that characterizes HD.

DOI: 10.7554/eLife.64564
PMID: 33871358

Comparison in Drosophila of 13 different human RASopathy isoforms points to differences in pathways affected and therapeutic responses

iScience. 2021 Mar 13;24(4):102306. doi: 10.1016/j.isci.2021.102306.

Drosophila RASopathy models identify disease subtype differences and biomarkers of drug efficacy.

Das TK, Gatto J, Mirmira R, Hourizadeh E, Kaufman D, Gelb BD, Cagan R

Abstract:

RASopathies represent a family of mostly autosomal dominant diseases that are caused by missense variants in the rat sarcoma viral oncogene/mitogen activated protein kinase (RAS/MAPK) pathway including KRAS, NRAS, BRAF, RAF1, and SHP2. These variants are associated with overlapping but distinct phenotypes that affect the heart, craniofacial, skeletal, lymphatic, and nervous systems. Here, we report an analysis of 13 Drosophila transgenic lines, each expressing a different human RASopathy isoform. Similar to their human counterparts, each Drosophila line displayed common aspects but also important differences including distinct signaling pathways such as the Hippo and SAPK/JNK signaling networks. We identified multiple classes of clinically relevant drugs-including statins and histone deacetylase inhibitors-that improved viability across most RASopathy lines; in contrast, several canonical RAS pathway inhibitors proved less broadly effective. Overall, our study compares and contrasts a large number of RASopathy-associated variants including their therapeutic responses.

DOI: 10.1016/j.isci.2021.102306
PMCID: PMC8026909
PMID: 33855281

Conflict of interest statement: B.G. declares royalties from GeneDx, Correlegan, LabCorp, and Prevention Genetics. B.G. is a named inventor on issued patents related to PTPN11, SHOC2, RAF1, and SOS1 mutations in Noonan syndrome. The Icahn School of Medicine at Mount Sinai licensed the patent to several diagnostics companies and has received royalty payments, some of which are distributed to B.G. B.G. and R.C. are principal investigators for a sponsored research agreement from Onconova.

Study looks at molecular mechsnisms underlying circadian rhythm disruption in fly model of Fragile X syndrome

Neurosci Bull. 2021 Apr 15. doi: 10.1007/s12264-021-00682-z.

Dysregulated CRMP Mediates Circadian Deficits in a Drosophila Model of Fragile X Syndrome.

Zhao J, Xue J, Zhu T, He H, Kang H, Jiang X, Huang W, Duan R

Abstract:

Fragile X syndrome (FXS) is the leading inherited cause of intellectual disability, resulting from the lack of functional fragile X mental retardation protein (FMRP), an mRNA binding protein mainly serving as a translational regulator. Loss of FMRP leads to dysregulation of target mRNAs. The Drosophila model of FXS show an abnormal circadian rhythm with disruption of the output pathway downstream of the clock network. Yet the FMRP targets involved in circadian regulation have not been identified. Here, we identified collapsing response mediator protein (CRMP) mRNA as a target of FMRP. Knockdown of pan-neuronal CRMP expression ameliorated the circadian defects and abnormal axonal structures of clock neurons (ventral lateral neurons) in dfmr1 mutant flies. Furthermore, specific reduction of CRMP in the downstream output insulin-producing cells attenuated the aberrant circadian behaviors. Molecular analyses revealed that FMRP binds with CRMP mRNA and negatively regulates its translation. Our results indicate that CRMP is an FMRP target and establish an essential role for CRMP in the circadian output in FXS Drosophila.

DOI: 10.1007/s12264-021-00682-z
PMID: 33856646

Light-activated receptors tested in Drosophila model of Parkinson's disease

PLoS Genet. 2021 Apr 15;17(4):e1009479. doi: 10.1371/journal.pgen.1009479.

Optogenetic delivery of trophic signals in a genetic model of Parkinson's disease.

Ingles-Prieto A, Furthmann N, Crossman SH Tichy AM, Hoyer N, Petersen M, Zheden V, Biebl J, Reichhart E, Gyoergy A, Siekhaus DE, Soba P, Winklhofer KF, Janovjak H

Abstract:

Optogenetics has been harnessed to shed new mechanistic light on current and future therapeutic strategies. This has been to date achieved by the regulation of ion flow and electrical signals in neuronal cells and neural circuits that are known to be affected by disease. In contrast, the optogenetic delivery of trophic biochemical signals, which support cell survival and are implicated in degenerative disorders, has never been demonstrated in an animal model of disease. Here, we reengineered the human and Drosophila melanogaster REarranged during Transfection (hRET and dRET) receptors to be activated by light, creating one-component optogenetic tools termed Opto-hRET and Opto-dRET. Upon blue light stimulation, these receptors robustly induced the MAPK/ERK proliferative signaling pathway in cultured cells. In PINK1B9 flies that exhibit loss of PTEN-induced putative kinase 1 (PINK1), a kinase associated with familial Parkinson's disease (PD), light activation of Opto-dRET suppressed mitochondrial defects, tissue degeneration and behavioral deficits. In human cells with PINK1 loss-of-function, mitochondrial fragmentation was rescued using Opto-dRET via the PI3K/NF-кB pathway. Our results demonstrate that a light-activated receptor can ameliorate disease hallmarks in a genetic model of PD. The optogenetic delivery of trophic signals is cell type-specific and reversible and thus has the potential to inspire novel strategies towards a spatio-temporal regulation of tissue repair.

DOI: 10.1371/journal.pgen.1009479
PMID: 33857132

Fly model related to FIG-4 associated neurological disorders uncovers potential link to epigenetic regulation

Neuroreport. 2021 May 5;32(7):562-568. doi: 10.1097/WNR.0000000000001636.

Identification of Rpd3 as a novel epigenetic regulator of Drosophila FIG 4, a
Charcot-Marie-Tooth disease-causing gene.

Muraoka Y, Nikaido A, Kowada R, Kimura H, Yamaguchi M, Yoshida H

Abstract:

Mutations in the factor-induced-gene 4 (FIG 4) gene are associated with multiple disorders, including Charcot-Marie-Tooth disease (CMT), epilepsy with polymicrogyria, Yunis-Varón syndrome and amyotrophic lateral sclerosis. The wide spectrum of disorders associated with FIG 4 may be related to the dysregulated epigenetics. Using Gene Expression Omnibus, we found that HDAC1 binds to the FIG 4 gene locus in the genome of human CD4+ T cells. Rpd3 is a well-known Drosophila homolog of human HDAC1. We previously established Drosophila models targeting Drosophila FIG 4 (dFIG 4) that exhibited defective locomotive ability, abnormal synapse morphology at neuromuscular junctions, enlarged vacuoles in the fat body and aberrant compound eye morphology. Genetic crossing experiments followed by physiological and immunocytochemical analyses revealed that Rpd3 mutations suppressed these defects induced by dFIG 4 knockdown. This demonstrated Rpd3 to be an important epigenetic regulator of dFIG 4, suggesting that the inhibition of HDAC1 represses the pathogenesis of FIG 4-associated disorders, including CMT. Defects in epigenetic regulators, such as HDAC1, may also explain the diverse symptoms of FIG 4-associated disorders.

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

DOI: 10.1097/WNR.0000000000001636
PMID: 33850086

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