The InteractiveFly: Drosophila as a Model for Human Diseases


Miscellaneous Drosophila Disease Models

Miscellaneous Drosophila Disease Models

Adrenoleukodystrophy

Adult-onset inherited myopathy

Charcot-Marie-Tooth Disease 4J

Colorectal cancer

Congenital disorders of glycosylation

Episodic ataxia

Friedrich's ataxia, a recessive neurodegeneration disorder

Galactosemia

Human papillomavirus E6-induced malignancy

Inclusion body myopathy type 3

Intellectual Disability associated with WAC

Kohlschutter-Tonz syndrome

Lysosomal storage disease

Mitochondrial encephalomyopathy

Myeloproliferative neoplasms

Myotonic Dystrophy

Nephrotic Syndrome

Nonsyndromic X-linked mental retardation

Perry syndrome

Polyglutamine (polyQ) disorders

Prion disease

Retinitis pigmentosa

Skin cancer and nucleotide excision repair

Spinal muscular atrophy

Spinocerebellar ataxia

Squamous cell carcinoma
Adrenoleukodystrophy

Sivachenko, A., Gordon, H. B., Kimball, S. S., Gavin, E. J., Bonkowsky, J. L. and Letsou, A. (2016). Neurodegeneration in a Drosophila model of Adrenoleukodystrophy: the roles of the bubblegum and double bubble acyl-CoA synthetases. Dis Model Mech 9(4): 377-87. PubMed ID:
26893370

Abstract
Debilitating neurodegenerative conditions with metabolic origins affect millions of individuals worldwide. Still, for most of these neurometabolic disorders there are neither cures nor disease- modifying therapies, and novel animal models are needed for elucidation of disease pathology and identification of potential therapeutic agents. This study presents the first analysis of a very long chain acyl-CoA synthetase double mutant. The Drosophila bubblegum (bgm) and double bubble (dbb) genes have overlapping functions, and the consequences of bubblegum double bubble double knockout in the fly brain are profound, affecting behavior and brain morphology, and providing the best paradigm to date for an animal model of Adrenoleukodystrophy (ALD), a fatal childhood neurodegenerative disease associated with the accumulation of very long chain fatty acids. Using this more fully penetrant model of disease to interrogate brain morphology at the level of electron microscopy, this study shows that dysregulation of fatty acid metabolism via disruption of ACS function in vivo is causal of neurodegenerative pathologies evident in both neuronal cells and their support cell populations, and leads ultimately to lytic cell death in affected areas of the brain. Finally, in an extension of the model system to the study of human disease, identification of a leukodystrophy patient who harbors a rare mutation in a human homologue of Bgm and Dbb was found: the SLC27a6-encoded very-long-chain acyl-CoA synthetase.

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Adult-onset inherited myopathy

Li, S., Zhang, P., Freibaum, B.D., Kim, N.C., Kolaitis, R.M., Molliex, A., Kanagaraj, A.P., Yabe, I., Tanino, M., Tanaka, S., Sasaki, H., Ross, E.D., Taylor, J.P. and Kim, H.J. (2016). Genetic interaction of hnRNPA2B1 and DNAJB6 in a Drosophila model of multisystem proteinopathy. Hum Mol Genet 25(5): 936-50. PubMed ID:
26744327

Abstract
This study sought to establish a mechanistic link between diseases caused by mutations in two genes associated with adult-onset inherited myopathies, hnRNPA2B1 and DNAJB6. Hrb98DE and mrj are the Drosophila homologs of human hnRNPA2B1 and DNAJB6, respectively. Disease-homologous mutations were introduced to Hrb98DE. Ectopic expression of the disease-associated mutant form of hnRNPA2B1 or Hrb98DE in fly muscle resulted in progressive, age-dependent cytoplasmic inclusion pathology, as observed in humans with hnRNPA2B1-related myopathy. Cytoplasmic inclusions consisted of hnRNPA2B1 or Hrb98DE protein in association with the stress granule marker ROX8 and additional endogenous RNA-binding proteins, suggesting that these pathological inclusions are related to stress granules. Notably, TDP-43 was also recruited to these cytoplasmic inclusions. Remarkably, overexpression of MRJ rescued this phenotype and suppressed the formation of cytoplasmic inclusions, whereas reduction of endogenous MRJ by a classical loss of function allele enhanced it. Moreover wild-type, but not disease-associated mutant forms of MRJ, interacted with RNA-binding proteins after heat shock and prevented their accumulation in aggregates. These results indicate both genetic and physical interaction between disease-linked RNA-binding proteins and DNAJB6/mrj, suggesting etiologic overlap between the pathogenesis of hIBM and LGMD initiated by mutations in hnRNPA2B1 and DNAJB6.

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Charcot-Marie-Tooth Disease 4J

Bharadwaj, R., Cunningham, K. M., Zhang, K. and Lloyd, T. E.
(2015). FIG4 regulates lysosome membrane homeostasis independent of phosphatase function. Hum Mol Genet 25(4): 681-92. PubMed ID: 26662798

Abstract
FIG4 is a phosphoinositide phosphatase that is mutated in several diseases including Charcot-Marie-Tooth Disease 4J (CMT4J) and Yunis-Varon syndrome (YVS). To investigate the mechanism of disease pathogenesis, Drosophila models were generated of FIG4-related diseases. Fig4 null mutant flies are viable but exhibit marked enlargement of the lysosomal compartment in muscle cells and neurons, accompanied by an age-related decline in flight ability. Transgenic animals expressing Drosophila Fig4 missense mutations corresponding to human pathogenic mutations can partially rescue lysosomal expansion phenotypes, consistent with these mutations causing decreased FIG4 function. Interestingly, Fig4 mutations predicted to inactivate FIG4 phosphatase activity rescue lysosome expansion phenotypes, and mutations in the phosphoinositide (3) phosphate kinase Fab1 that performs the reverse enzymatic reaction also causes a lysosome expansion phenotype. Since FIG4 and FAB1 are present together in the same biochemical complex, these data are consistent with a model in which FIG4 serves a phosphatase-independent biosynthetic function that is essential for lysosomal membrane homeostasis. Lysosomal phenotypes are suppressed by genetic inhibition of Rab7 or the HOPS complex, demonstrating that FIG4 functions after endosome-to-lysosome fusion. Furthermore, disruption of the retromer complex, implicated in recycling from the lysosome to Golgi, does not lead to similar phenotypes as Fig4, suggesting that the lysosomal defects are not due to compromised retromer-mediated recycling of endolysosomal membranes. These data show that FIG4 plays a critical noncatalytic function in maintaining lysosomal membrane homeostasis, and that this function is disrupted by mutations that cause CMT4J and YVS.

Atkinson, D., Nikodinovic Glumac, J., Asselbergh, B., Ermanoska, B., Blocquel, D., Steiner, R., Estrada-Cuzcano, A., Peeters, K., Ooms, T., De Vriendt, E., Yang, X. L., Hornemann, T., Milic Rasic, V. and Jordanova, A. (2017). Sphingosine 1-phosphate lyase deficiency causes Charcot-Marie-Tooth neuropathy. Neurology [Epub ahead of print]. PubMed ID: 28077491

Abstract
This study sought to identify the unknown genetic cause in a family with an axonal form of peripheral neuropathy and atypical disease course. Both patients presented an atypical form of axonal peripheral neuropathy, characterized by acute or subacute onset and episodes of recurrent mononeuropathy. Compound heterozygous mutations were identified cosegregating with disease that were absent in controls in the SGPL1 gene, encoding sphingosine 1-phosphate lyase (SPL). The p.Ser361* mutation triggers nonsense-mediated mRNA decay. The missense p.Ile184Thr mutation causes partial protein degradation. The plasma levels of sphingosine 1-phosphate and sphingosine/sphinganine ratio were increased in the patients. Neuron-specific downregulation of the Drosophila orthologue, Sphingosine-1-phosphate lyase impaired the morphology of the neuromuscular junction and caused progressive degeneration of the chemosensory neurons innervating the wing margin bristles. It is suggested that SPL deficiency is a cause of a distinct form of Charcot-Marie-Tooth disease in humans, thus extending the currently recognized clinical and genetic spectrum of inherited peripheral neuropathies. These data emphasize the importance of sphingolipid metabolism for neuronal function.

Kyotani, A., Azuma, Y., Yamamoto, I., Yoshida, H., Mizuta, I., Mizuno, T., Nakagawa, M., Tokuda, T. and Yamaguchi, M. (2015). Knockdown of the Drosophila FIG4 induces deficient locomotive behavior, shortening of motor neuron, axonal targeting aberration, reduction of life span and defects in eye development. Exp Neurol [Epub ahead of print]. PubMed ID: 26708557

Abstract
Mutations in Factor-Induced-Gene 4 (FIG4) gene have been identified in Charcot-Marie-Tooth disease type 4J (CMT4J), Yunis-Varon syndrome and epilepsy with polymicrogyria. FIG4 protein regulates a cellular abundance of phosphatidylinositol 3,5-bisphosphate (PI3,5P2), a signaling lipid on the cytosolic surface of membranes of the late endosomal compartment. PI3,5P2 is required for retrograde membrane trafficking from lysosomal and late endosomal compartments to the Golgi. However, it is still unknown how the neurodegeneration that occurs in these diseases is related to the loss of FIG4 function. Drosophila has CG17840 (dFIG4) as a human FIG4 homologue. This study specifically knocked down dFIG4 in various tissues, and investigated their phenotypes. Neuron-specific knockdown of dFIG4 results in axonal targeting aberrations of photoreceptor neurons, shortened presynaptic terminals of motor neurons in 3rd instar larvae and reduced climbing ability in adulthood and life span. Fat body-specific knockdown of dFIG4 results in enlarged lysosomes in cells that were detected by staining with LysoTracker. In addition, eye imaginal disc-specific knockdown of dFIG4 disrupts differentiation of pupal ommatidial cell types, such as cone cells and pigment cells, suggesting an additional role of dFIG4 during eye development (Kyotani, 2015).

Lopez Del Amo, V., Palomino-Schatzlein, M., Seco-Cervera, M., Garcia-Gimenez, J. L., Pallardo, F. V., Pineda-Lucena, A. and Galindo, M. I. (2017). A Drosophila model of GDAP1 function reveals the involvement of insulin signalling in the mitochondria-dependent neuromuscular degeneration. Biochim Biophys Acta 1863(3): 801-809. PubMed ID: 28065847

Abstract
Charcot-Marie-Tooth disease is a rare peripheral neuropathy for which there is no specific treatment. Some forms of Charcot-Marie-Tooth are due to mutations in the GDAP1 gene. A striking feature of mutations in GDAP1 is that they have a variable clinical manifestation, according to disease onset and progression, histology and mode of inheritance. Studies in cellular and animal models have revealed a role of GDAP1 in mitochondrial morphology and distribution, calcium homeostasis and oxidative stress. To get a better understanding of the disease mechanism, this study generated models of over-expression and RNA interference of the Drosophila Gdap1 gene. In order to get an overview about the changes that Gdap1 mutations cause in this disease model, a comprehensive determination of the metabolic profile in the flies by nuclear magnetic resonance spectroscopy was combined with gene expression analyses and biophysical tests. The results revealed that both up- and down-regulation of Gdap1 results in an early systemic inactivation of the insulin pathway before the onset of neuromuscular degeneration, followed by an accumulation of carbohydrates and an increase in the beta-oxidation of lipids. These findings are in line with emerging reports of energy metabolism impairments linked to different types of neural pathologies caused by defective mitochondrial function, which is not surprising given the central role of mitochondria in the control of energy metabolism. The relationship of mitochondrial dynamics with metabolism during neurodegeneration opens new avenues to understand the cause of the disease, and for the discovery of new biomarkers and treatments.

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Colorectal cancer

Bangi, E., Murgia, C., Teague, A.G., Sansom, O.J. and Cagan, R.L. (2016). Functional exploration of colorectal cancer genomes using Drosophila. Nat Commun 7: 13615. PubMed ID:
27897178

Abstract

The multigenic nature of human tumours presents a fundamental challenge for cancer drug discovery. This study used Drosophila to generate 32 multigenic models of colon cancer using patient data from The Cancer Genome Atlas. These models recapitulate key features of human cancer, often as emergent properties of multigenic combinations. Multigenic models such as ras p53 pten apc exhibit emergent resistance to a panel of cancer-relevant drugs. Exploring one drug in detail, a mechanism of resistance for the PI3K pathway inhibitor BEZ235 was identified. Based on this, a combinatorial therapy that circumvents this resistance through a two-step process of emergent pathway dependence and sensitivity termed 'induced dependence' was developed. This approach is effective in cultured human tumour cells, xenografts and mouse models of colorectal cancer. These data demonstrate how multigenic animal models that reference cancer genomes can provide an effective approach for developing novel targeted therapies (Bangi, 2016).

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Congenital disorders of glycosylation

Parkinson, W. M., Dookwah, M., Dear, M. L., Gatto, C. L., Aoki, K., Tiemeyer, M. and Broadie, K. (2016). Neurological roles for phosphomannomutase type 2 in a new Drosophila congenital disorder of glycosylation disease model. Dis Model Mech [Epub ahead of print]. PubMed ID:
26940433

Abstract

The most common Congenital disorders of glycosylation (CDGs), CDG-Ia or PMM2-CDG, arises from phosphomannomutase type 2 (PMM2) mutations. This study reports the generation and characterization of the first Drosophila PMM2-CDG model. CRISPR-generated Drosophila pmm2 null mutants display severely disrupted glycosylation and early lethality, while RNAi-targeted neuronal PMM2 knockdown results in a strong shift in pauci-mannose glycan abundance, progressive incoordination and later lethality, closely paralleling human CDG-Ia symptoms of shortened lifespan, movement impairments and defective neural development. Analyses of the well-characterized Drosophila neuromuscular junction (NMJ) reveal synaptic glycosylation loss accompanied by structural architecture and functional neurotransmission defects. NMJ synaptogenesis is driven by intercellular signals traversing an extracellular synaptomatrix co-regulated by glycosylation and matrix metalloproteinases (MMPs). Specifically, Wnt Wingless (Wg) trans-synaptic signaling depends on the heparan sulfate proteoglycan (HSPG) co-receptor Dally-like protein (Dlp), which is regulated by synaptic MMP activity. Loss of synaptic MMP2, Wg ligand, Dlp co-receptor and downstream trans-synaptic signaling occurs with PMM2 knockdown. Taken together, this Drosophila CDG disease model provides a new avenue for the dissection of cellular and molecular mechanisms underlying neurological impairments and a means to discover and test novel therapeutic treatment strategies.

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Episodic Ataxia

Parinejad, N., Peco, E., Ferreira, T., Stacey, S.M. and van Meyel, D.J. (2016).Disruption of an EAAT-mediated chloride channel in a Drosophila model of Ataxia. J Neurosci 36: 7640-7647. PubMed ID: 27445142

Abstract
Patients with Type 6 episodic ataxia (EA6) have mutations of the excitatory amino acid transporter EAAT1 (also known as GLAST), but the underlying pathophysiological mechanism for EA6 is not known. EAAT1 is a glutamate transporter expressed by astrocytes and other glia, and it serves dual function as an anion channel. One EA6-associated mutation is a P>R substitution (EAAT1(P>R)) that in transfected cells has a reduced rate of glutamate transport and an abnormal anion conductance. This study expressed this EAAT1(P>R) mutation in glial cells of Drosophila larvae and found that these larvae exhibit episodic paralysis, and their astrocytes poorly infiltrate the CNS neuropil. These defects are not seen in Eaat1-null mutants, and so they cannot be explained by loss of glutamate transport. To explore the role of the abnormal anion conductance of the EAAT1(P>R) mutation, chloride cotransporters were expressed in astrocytes. Like the EAAT1(P>R) mutation, the chloride-extruding K(+)-Cl(-) cotransporter KccB also causes astroglial malformation and paralysis, supporting the idea that the EAAT1(P>R) mutation causes abnormal chloride flow from CNS glia. In contrast, the Na(+)-K(+)-Cl(-) cotransporter Ncc69, which normally allows chloride into cells, rescues the effects of the EAAT1(P>R) mutation. Together, these results indicate that the cytopathology and episodic paralysis in the Drosophila EA6 model stem from a gain-of-function chloride channelopathy of glial cells.

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Friedrich's ataxia, a recessive neurodegeneration disorder

Chen, K., Lin, G., Haelterman, N.A., Ho, T.S., Li, T., Li, Z., Duraine, L., Graham, B.H., Jaiswal, M., Yamamoto, S., Rasband, M.N. and Bellen, H.J. (2016). Loss of Frataxin induces iron toxicity, sphingolipid synthesis, and Pdk1/Mef2 activation, leading to neurodegeneration. Elife [Epub ahead of print]. PubMed ID: 27343351

Abstract
Mutations in Frataxin (FXN) cause Friedreich's ataxia (FRDA), a recessive neurodegenerative disorder. Previous studies have proposed that loss of FXN causes mitochondrial dysfunction, which triggers elevated reactive oxygen species (ROS) and leads to the demise of neurons. This study describes a ROS independent mechanism that contributes to neurodegeneration in fly FXN mutants. Loss of frataxin homolog (fh) in Drosophila was shown to leads to iron toxicity, which in turn induces sphingolipid synthesis and ectopically activates 3-phosphoinositide dependent protein kinase-1 (Pdk1) and myocyte enhancer factor-2 (Mef2). Dampening iron toxicity, inhibiting sphingolipid synthesis by Myriocin, or reducing Pdk1 or Mef2 levels, all effectively suppress neurodegeneration in fh mutants. Moreover, increasing dihydrosphingosine activates Mef2 activity through PDK1 in mammalian neuronal cell line suggesting that the mechanisms are evolutionarily conserved. These results indicate that an iron/sphingolipid/PDk1/Mef2 pathway may play a role in FRDA.

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Galactosemia

Jumbo-Lucioni, P. P., Parkinson, W. M., Kopke, D. L. and Broadie, K. (2016). Coordinated movement, neuromuscular synaptogenesis and trans-synaptic signaling defects in Drosophila galactosemia models. Hum Mol Genet [Epub ahead of print]. PubMed ID: 27466186

Abstract

The multiple galactosemia disease states manifest long-term neurological symptoms. Galactosemia I results from loss of galactose-1-phosphate uridyltransferase (GALT), which converts galactose-1-phosphate + UDP-glucose to glucose-1-phosphate + UDP-galactose. Galactosemia II results from loss of galactokinase (GALK), phosphorylating galactose to galactose-1-phosphate. Galactosemia III results from the loss of UDP-galactose 4'-epimerase (GALE), which interconverts UDP-galactose and UDP-glucose, as well as UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine. UDP-glucose pyrophosphorylase (UGP) alternatively makes UDP-galactose from uridine triphosphate and galactose-1-phosphate. All four UDP-sugars are essential donors for glycoprotein biosynthesis with critical roles at the developing neuromuscular synapse. Drosophila galactosemia I (dGALT) and II (dGALK) disease models genetically interact; manifesting deficits in coordinated movement, neuromuscular junction (NMJ) development, synaptic glycosylation, and Wnt trans-synaptic signaling. Similarly, dGALE and dUGP mutants display striking locomotor and NMJ formation defects, including expanded synaptic arbors, glycosylation losses, and differential changes in Wnt trans-synaptic signaling. In combination with dGALT loss, both dGALE and dUGP mutants compromise the synaptomatrix glycan environment that regulates Wnt trans-synaptic signaling that drives 1) presynaptic Futsch/MAP1b microtubule dynamics and 2) postsynaptic Frizzled nuclear import (FNI). Taken together, these findings indicate UDP-sugar balance is a key modifier of neurological outcomes in all three interacting galactosemia disease models, suggest that Futsch homolog MAP1B and the Wnt Frizzled receptor may be disease-relevant targets in epimerase and transferase galactosemias, and identify UGP as promising new potential therapeutic target for galactosemia neuropathology (Jumbo-Lucioni, 2016).

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Human papillomavirus E6-induced malignancy

Padash Barmchi, M., Gilbert, M., Thomas, M., Banks, L., Zhang, B. and Auld, V. J. (2016). A Drosophila model of HPV E6-induced malignancy reveals essential roles for Magi and the Insulin Receptor. PLoS Pathog 12: e1005789. PubMed ID: 27537218

Abstract

The causative agents of cervical cancers, high-risk human papillomaviruses (HPVs), cause cancer through the action of two oncoproteins, E6 and E7. The E6 oncoprotein cooperates with an E3 ubiquitin ligase (UBE3A; see Drosophila Ube3a) to target the p53 tumour suppressor and important polarity and junctional PDZ proteins for proteasomal degradation. However, the causative link between degradation of PDZ proteins and E6-mediated malignancy is largely unknown. An in vivo model of HPV E6-mediated cellular transformation was developed using Drosophila as model. Co-expression of E6 and human UBE3A in wing and eye epithelia results in severe morphological abnormalities. Furthermore, E6, via its PDZ-binding motif and in cooperation with UBE3A, targets a suite of PDZ proteins, including Magi, Dlg and Scribble. Similar to human epithelia, Drosophila Magi is a major degradation target. Magi overexpression rescues the cellular abnormalities caused by E6+UBE3A coexpression and this activity of Magi is PDZ domain-dependent. Tumorigenesis occurred when E6+UBE3A are expressed in conjunction with activated/oncogenic forms of Ras or Notch. This study identified the insulin receptor signaling pathway as being required for E6+UBE3A induced hyperplasia. These results suggest a highly conserved mechanism of HPV E6 mediated cellular transformation (Padash Barmchi, 2016).

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Inclusion body myopathy type 3

Suggs, J. A., Melkani, G. C., Glasheen, B. M., Detor, M. M., Melkani, A., Marsan, N. P., Swank, D. M. and Bernstein, S. I. (2017). A Drosophila model of dominant inclusion body myopathy 3 shows diminished myosin kinetics that reduce muscle power and yield myofibrillar defects. Dis Model Mech [Epub ahead of print]. PubMed ID: 28258125

Abstract

Inclusion body myopathy type 3 (IBM-3) patients display congenital joint contractures with early-onset muscle weakness that becomes more severe in adults. The disease arises from an autosomal dominant point mutation causing an E706K substitution in myosin heavy chain type IIa. The corresponding myosin mutation (E701K) in Drosophila Myosin was expressed in homozygous Drosophila indirect flight muscles and the myofibrillar degeneration and inclusion bodies observed in the human disease was recapitulated. Purified E701K myosin has dramatically reduced actin-sliding velocity and ATPase levels. Since IBM-3 is a dominant condition, the disease state was examined in heterozygote Drosophila in order to gain a mechanistic understanding of E701K pathogenicity. Myosin ATPase activities in heterozygotes suggest that approximately equimolar levels of myosin accumulate from each allele. In vitro actin sliding velocity rates for myosin isolated from the heterozygotes were lower than the control, but higher than for the pure mutant isoform. Although sarcomeric ultrastructure was nearly wild-type in young adults, mechanical analysis of skinned indirect flight muscle fibers revealed an 85% decrease in maximum oscillatory power generation and an approximately 6-fold reduction in the frequency at which maximum power was produced. Rate constant analyses suggest a decrease in the rate of myosin attachment to actin, with myosin spending decreased time in the strongly bound state. These mechanical alterations result in a one third decrease in wing beat frequency and marginal flight ability. With aging, muscle ultrastructure and function progressively declined. Aged myofibrils showed Z-line streaming, consistent with the human heterozygote phenotype. Based upon the mechanical studies, it is hypothesize that the mutation decreases the probability of the power stroke occurring and/or alters the degree of movement of the myosin lever arm, resulting in decreased in vitro motility, reduced muscle power output and focal myofibrillar disorganization similar to that seen in human IBM-3 patients (Suggs, 2017).

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Intellectual Disability associated with WAC

Lugtenberg, D., et al. (2016). De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila. Eur J Hum Genet. PubMed ID: 26757981

Abstract
Recently WAC was reported as a candidate gene for intellectual disability (ID) based on the identification of a de novo mutation in an individual with severe ID. WAC regulates transcription-coupled histone H2B ubiquitination and has previously been implicated in the 10p12p11 contiguous gene deletion syndrome. This study reports on 10 individuals with de novo WAC mutations which were identified through routine (diagnostic) exome sequencing and targeted resequencing of WAC in 2326 individuals with unexplained ID. All but one mutation was expected to lead to a loss-of-function of WAC. Clinical evaluation of all individuals revealed phenotypic overlap for mild ID, hypotonia, behavioral problems and distinctive facial dysmorphisms, including a square-shaped face, deep set eyes, long palpebral fissures, and a broad mouth and chin. These clinical features were also previously reported in individuals with 10p12p11 microdeletion syndrome. To investigate the role of WAC in ID, the importance of the Drosophila WAC orthologue (CG8949) was studied in habituation, a non-associative learning paradigm. Neuronal knockdown of Drosophila CG8949 resulted in impaired learning, suggesting that WAC is required in neurons for normal cognitive performance. In conclusion, this study has defined a clinically recognizable ID syndrome, caused by de novo loss-of-function mutations in WAC. Independent functional evidence in Drosophila further supported the role of WAC in ID. On the basis of these data WAC can be added to the list of ID genes with a role in transcription regulation through histone modification (Lugtenberg,, 2016).

David-Morrison, G., Xu, Z., Rui, Y.N., Charng, W.L., Jaiswal, M., Yamamoto, S., Xiong, B., Zhang, K., Sandoval, H., Duraine, L., Zuo, Z., Zhang, S. and Bellen, H.J. (2016). WAC regulates mTOR activity by acting as an adaptor for the TTT and Pontin/Reptin complexes. Dev Cell 36: 139-151. PubMed ID: 26812014

Abstract
The ability to sense energy status is crucial in the regulation of metabolism via the mechanistic Target of Rapamycin Complex 1 (mTORC1). The assembly of the TTT-Pontin/Reptin complex is responsive to changes in energy status. Under energy-sufficient conditions, the TTT-Pontin/Reptin complex promotes mTORC1 dimerization and mTORC1-Rag interaction, which are critical for mTORC1 activation. This study shows that WAC is a regulator of energy-mediated mTORC1 activity. In a Drosophila screen designed to isolate mutations that cause neuronal dysfunction, wacky, the homolog of WAC, was identified. Loss of Wacky leads to neurodegeneration, defective mTOR activity, and increased autophagy. Wacky and WAC have conserved physical interactions with mTOR and its regulators, including Pontin and Reptin, which bind to the TTT complex to regulate energy-dependent activation of mTORC1. WAC promotes the interaction between TTT and Pontin/Reptin in an energy-dependent manner, thereby promoting mTORC1 activity by facilitating mTORC1 dimerization and mTORC1-Rag interaction (David-Morrison, 2016).

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Kohlschutter-Tonz syndrome

Kim, M., Jang, D., Yoo, E., Oh, Y., Sonn, J. Y., Lee, J., Ki, Y., Son, H. J., Hwang, O., Lee, C., Lim, C. and Choe, J. (2017). Rogdi defines GABAergic control of a wake-promoting dopaminergic pathway to sustain sleep in Drosophila. Sci Rep 7(1): 11368. PubMed ID:
28900300

Abstract

Kohlschutter-Tonz syndrome (KTS) is a rare genetic disorder with neurological dysfunctions including seizure and intellectual impairment. Mutations at the Rogdi locus have been linked to development of KTS, yet the underlying mechanisms remain elusive. This study demonstrates that a Drosophila homolog of Rogdi acts as a novel sleep-promoting factor by supporting a specific subset of gamma-aminobutyric acid (GABA) transmission. Rogdi mutant flies displayed insomnia-like behaviors accompanied by sleep fragmentation and delay in sleep initiation. The sleep suppression phenotypes were rescued by sustaining GABAergic transmission primarily via metabotropic GABA receptors or by blocking wake-promoting dopaminergic pathways. Transgenic rescue further mapped GABAergic neurons as a cell-autonomous locus important for Rogdi-dependent sleep, implying metabotropic GABA transmission upstream of the dopaminergic inhibition of sleep. Consistently, an agonist specific to metabotropic but not ionotropic GABA receptors titrated the wake-promoting effects of dopaminergic neuron excitation. Taken together, these data provide the first genetic evidence that implicates Rogdi in sleep regulation via GABAergic control of dopaminergic signaling. Given the strong relevance of GABA to epilepsy, it is proposed that similar mechanisms might underlie the neural pathogenesis of Rogdi-associated KTS (Kim, 2017).

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Lysosomal storage disease

Hindle, S. J., Hebbar, S., Schwudke, D., Elliott, C. J. and Sweeney, S. T. (2017). A saposin deficiency model in Drosophila: Lysosomal storage, progressive neurodegeneration and sensory physiological decline. Neurobiol Dis. PubMed ID:
27913291

Abstract

Saposin deficiency is a childhood neurodegenerative lysosomal storage disorder (LSD) that can cause premature death within three months of life. Saposins are activator proteins that promote the function of lysosomal hydrolases that mediate the degradation of sphingolipids. Mutations causing an absence or impaired function of saposins in humans lead to distinct LSDs due to the storage of different classes of sphingolipids. The pathological events leading to neuronal dysfunction induced by lysosomal storage of sphingolipids are as yet poorly defined. A Drosophila model of saposin deficiency has been generated and characterised that shows striking similarities to the human diseases. Drosophila Saposin-related (dSap-r) mutants show a reduced longevity, progressive neurodegeneration, lysosomal storage, dramatic swelling of neuronal soma, perturbations in sphingolipid catabolism, and sensory physiological deterioration. These data suggests a genetic interaction with a calcium exchanger (Calx) pointing to a possible calcium homeostasis deficit in dSap-r mutants. Together these findings support the use of dSap-r mutants in advancing understanding of the cellular pathology implicated in saposin deficiency and related LSDs (Hindle, 2016).

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Sellin, J., et al. (2017). Characterization of Drosophila saposin-related mutants as a model for lysosomal sphingolipid storage diseases. Dis Model Mech [Epub ahead of print]. PubMed ID: 28389479

Abstract

Sphingolipidoses are inherited diseases belonging to the class of lysosomal storage diseases (LSDs), which are characterized by the accumulation of indigestible material in the lysosome caused by specific defects in the lysosomal degradation machinery. The digestion of intra-lumenal membranes within lysosomes is facilitated by lysosomal sphingolipid activator proteins (saposins), which are cleaved from a Prosaposin precursor. prosaposin mutations cause some of the severest forms of sphingolipidoses, and are associated with perinatal lethality in mice, hampering studies on disease progression.This study identified the Drosophila Prosaposin orthologue Saposin-related (Sap-r) as a key regulator of lysosomal lipid homeostasis in the fly. Its mutation leads to a typical spingolipidosis phenotype with enlarged endo-lysosomal compartment and sphingolipid accumulation as shown by mass spectrometry and thin layer chromatography. sap-r mutants show reduced viability with approximately 50% adult survivors, allowing study of progressive neurodegeneration and analysis thelipid profile in young and aged flies. Additionally, a defect was observed in sterol homeostasis with local sterol depletion at the plasma membrane. Furthermore, autophagy was found to be increased, resulting in the accumulation of mitochondria in lysosomes, concomitant with increased oxidative stress. Together, this study establishes Drosophila sap-r mutants as a lysosomal storage disease model suitable for studying the age-dependent progression of lysosomal dysfunction associated with lipid accumulation and the resulting pathological signaling events (Sellin, 2017).

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Mitochondrial encephalomyopathy

Fogle, K.J., Hertzler, J.I., Shon, J.H. and Palladino, M.J. (2016). The ATP-sensitive K channel is seizure protective and required for effective dietary therapy in a model of mitochondrial encephalomyopathy. J Neurogenet [Epub ahead of print]. PubMed ID:
27868454

Abstract
MP27868454

Effective therapies are lacking for mitochondrial encephalomyopathies (MEs). MEs are devastating diseases that predominantly affect the energy-demanding tissues of the nervous system and muscle, causing symptoms such as seizures, cardiomyopathy, and neuro- and muscular degeneration. Even common anti-epileptic drugs which are frequently successful in ameliorating seizures in other diseases tend to have a lower success rate in ME, highlighting the need for novel drug targets, especially those that may couple metabolic sensitivity to neuronal excitability. Furthermore, alternative epilepsy therapies such as dietary modification are gaining in clinical popularity but have not been thoroughly studied in ME. Using the Drosophila ATP61 model of ME, this study analyzed dietary therapy throughout disease progression and found that it is highly effective against the seizures of ME, especially a high fat/ketogenic diet, and that the benefits are dependent upon a functional KATP channel complex. Further experiments with KATP show that it is seizure-protective in this model, and that pharmacological promotion of its open state also ameliorates seizures. These studies represent important steps forward in the development of novel therapies for a class of diseases that is notoriously difficult to treat, and lay the foundation for mechanistic studies of currently existing therapies in the context of metabolic disease (Fogle, 2016).

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Myeloproliferative neoplasms

Terriente-Félix, A., Pérez, L., Bray, S.J., Nebreda, A.R. and Milán, M. (2017). Drosophila model of myeloproliferative neoplasm reveals a feed-forward loop in the JAK pathway mediated by p38 MAPK signalling. Dis Model Mech [Epub ahead of print]. PubMed ID:
28237966

Abstract

Myeloproliferative neoplasms (MPNs) of the Philadelphia-negative class comprise polycythemia vera, essential thrombocythemia and primary myelofibrosis (PMF). They are associated with aberrant amounts of myeloid lineage cells in the blood, and in the case of overt PMF, with the development of myelofibrosis in the bone marrow and the failure to produce normal blood cells. These diseases are usually caused by gain-of-function mutations in the kinase JAK2. This study used Drosophila to investigate the consequences of activation of the JAK2 ortholog in hematopoiesis. The maturing hemocytes in the lymph gland, the major hematopoietic organ in the fly, was identified as the cell population susceptible to induce hypertrophy upon targeted overexpression of JAK. JAK was shown to activate a feed-forward loop including the cytokine-like ligand Upd3 and its receptor Domeless, which are required to induce lymph gland hypertrophy. Moreover, p38 MAPK signalling plays a key role in this process by inducing the expression of the ligand Upd3. Interestingly, forced activation of the p38 MAPK pathway in maturing hemocytes suffices to generate hypertrophic organs and the appearance of melanotic tumours. These results illustrate a novel pro-tumorigenic cross-talk between the p38 MAPK pathway and JAK signalling in a Drosophila model of MPNs. Based on the shared molecular mechanisms underlying MPNs in flies and humans, the interplay between Drosophila JAK and p38 signalling pathways unravelled in this work might have translational relevance for human MPNs (Terriente-Félix, 2017).

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Myotonic Dystrophy

Cerro-Herreros, E., Chakraborty, M., Perez-Alonso, M., Artero, R. and Llamusi, B.
(2017). Expanded CCUG repeat RNA expression in Drosophila heart and muscle trigger Myotonic Dystrophy type 1-like phenotypes and activate autophagocytosis genes. Sci Rep 7(1): 2843. PubMed ID: 28588248

Abstract

Myotonic dystrophies (DM1-2) are neuromuscular genetic disorders caused by the pathological expansion of untranslated microsatellites. DM1 and DM2, are caused by expanded CTG repeats in the 3'UTR of the DMPK gene and CCTG repeats in the first intron of the CNBP gene, respectively. Mutant RNAs containing expanded repeats are retained in the cell nucleus, where they sequester nuclear factors and cause alterations in RNA metabolism. However, for unknown reasons, DM1 is more severe than DM2. To study the differences and similarities in the pathogenesis of DM1 and DM2, model flies were generated by expressing pure expanded CUG ([250]x) or CCUG ([1100]x) repeats, respectively, and compared them with control flies expressing either 20 repeat units or GFP. Surprisingly, severe muscle reduction and cardiac dysfunction were observed in CCUG-expressing model flies. The muscle and cardiac tissue of both DM1 and DM2 model flies showed DM1-like phenotypes including overexpression of autophagy-related genes, RNA mis-splicing and repeat RNA aggregation in ribonuclear foci along with the Muscleblind protein. These data reveal, for the first time, that expanded non-coding CCUG repeat-RNA has similar in vivo toxicity potential as expanded CUG RNA in muscle and heart tissues and suggests that specific, as yet unknown factors, quench CCUG-repeat toxicity in DM2 patients (Cerro-Herreros, 2017).

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Nephrotic Syndrome

Hermle, T., Braun, D.A., Helmstädter, M., Huber, T.B. and Hildebrandt, F.
(2016). Modeling monogenic human nephrotic syndrome in the Drosophila garland cell nephrocyte J Am Soc Nephrol [Epub ahead of print]. PubMed ID: 27932481

Abstract

Steroid-resistant nephrotic syndrome is characterized by podocyte dysfunction. Drosophila garland cell nephrocytes are podocyte-like cells and thus provide a potential in vivo model in which to study the pathogenesis of nephrotic syndrome. However, relevant pathomechanisms of nephrotic syndrome have not been studied in nephrocytes. This study discovered that two Drosophila slit diaphragm proteins, orthologs of the human genes encoding nephrin and nephrin-like protein 1, colocalize within a fingerprint-like staining pattern that correlates with ultrastructural morphology. Using RNAi and conditional CRISPR/Cas9 in nephrocytes, it was found that this pattern depends on the expression of both orthologs. Tracer endocytosis by nephrocytes requires Cubilin and reflects size selectivity analogous to that of glomerular function. Using RNAi and tracer endocytosis as a functional read-out, Drosophila orthologs of human monogenic causes of nephrotic syndrome were screened and conservation of the central pathogenetic alterations was observed. It was found that the silencing of the coenzyme Q10 (CoQ10) biosynthesis gene Coq2 disrupts slit diaphragm morphology. Restoration of CoQ10 synthesis by vanillic acid partially rescues the phenotypic and functional alterations induced by Coq2-RNAi. Notably, Coq2 colocalizes with mitochondria, and Coq2 silencing increases the formation of reactive oxygen species (ROS). Silencing of ND75, a subunit of the mitochondrial respiratory chain that controls ROS formation independently of CoQ10, phenocopies the effect of Coq2-RNAi. Moreover, the ROS scavenger glutathione partially rescues the effects of Coq2-RNAi. In conclusion, Drosophila garland cell nephrocytes provide a model with which to study the pathogenesis of nephrotic syndrome, and ROS formation may be a pathomechanism of COQ2-nephropathy (Hermle, 2016).

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Nonsyndromic X-linked mental retardation

Liu, Z., Huang, Y., Hu, W., Huang, S., Wang, Q., Han, J. and Zhang, Y. Q.
(2014). dAcsl, the Drosophila ortholog of acyl-CoA synthetase long-chain family member 3 and 4, inhibits synapse growth by attenuating bone morphogenetic protein signaling via endocytic recycling. J Neurosci 34(8): 2785-2796. PubMed ID: 24553921

Abstract
Fatty acid metabolism plays an important role in brain development and function. Mutations in acyl-CoA synthetase long-chain family member 4 (ACSL4), which converts long-chain fatty acids to acyl-CoAs, result in nonsyndromic X-linked mental retardation. ACSL4 is highly expressed in the hippocampus, a structure critical for learning and memory. However, the underlying mechanism by which mutations of ACSL4 lead to mental retardation remains poorly understood. This study reports that dAcsl, the Drosophila ortholog of ACSL4 and ACSL3, inhibits synaptic growth by attenuating BMP signaling, a major growth-promoting pathway at neuromuscular junction (NMJ) synapses. Specifically, dAcsl mutants exhibited NMJ overgrowth that was suppressed by reducing the doses of the BMP pathway components, accompanied by increased levels of activated BMP receptor Thickveins (Tkv) and phosphorylated Mothers against decapentaplegic (Mad), the effector of the BMP signaling at NMJ terminals. In addition, Rab11, a small GTPase involved in endosomal recycling, was mislocalized in dAcsl mutant NMJs, and the membrane association of Rab11 was reduced in dAcsl mutant brains. Consistently, the BMP receptor Tkv accumulated in early endosomes but reduced in recycling endosomes in dAcsl mutant NMJs. dAcsl was also required for the recycling of photoreceptor rhodopsin in the eyes, implying a general role for dAcsl in regulating endocytic recycling of membrane receptors. Importantly, expression of human ACSL4 rescued the endocytic trafficking and NMJ phenotypes of dAcsl mutants. Together, these results reveal a novel mechanism whereby dAcsl facilitates Rab11-dependent receptor recycling and provide insights into the pathogenesis of ACSL4-related mental retardation (Liu, 2014).

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Perry Syndrome

Hosaka, Y., Inoshita, T., Shiba-Fukushima, K., Cui, C., Arano, T., Imai, Y. and Hattori, N.
(2017). Reduced TDP-43 expression improves neuronal activities in a Drosophila model of Perry syndrome. EBioMedicine [Epub ahead of print]. PubMed ID: 28625517

Abstract

Parkinsonian Perry syndrome, involving mutations in the dynein motor component dynactin or p150Glued, is characterized by TDP-43 pathology in affected brain regions, including the substantia nigra. However, the molecular relationship between p150Glued and TDP-43 is largely unknown. This study reports that a reduction in TDP-43 protein levels alleviates the synaptic defects of neurons expressing the Perry mutant p150G50R in Drosophila. Dopaminergic expression of p150G50R, which decreases dopamine release, disrupts motor ability and reduces the lifespan of Drosophila. p150G50R expression also causes aggregation of dense core vesicles (DCVs), which contain monoamines and neuropeptides, and disrupts the axonal flow of DCVs, thus decreasing synaptic strength. The above phenotypes associated with Perry syndrome are improved by the removal of a copy of Drosophila TDP-43, TBPH, thus suggesting that the stagnation of axonal transport by dynactin mutations promotes TDP-43 aggregation and interferes with the dynamics of DCVs and synaptic activities (Hosaka, 2017)

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Prion Disease

Thackray, A. M., Cardova, A., Wolf, H., Pradl, L., Vorberg, I., Jackson, W. S. and Bujdoso, R.
(2017). Genetic human prion disease modelled in PrP transgenic Drosophila. Biochem J 474(19): 3253-3267. PubMed ID: 28814578

Abstract

Inherited human prion diseases, such as fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD), are associated with autosomal dominant mutations in the human prion protein gene PRNP and accumulation of PrPSc, an abnormal isomer of the normal host protein PrPC, in the brain of affected individuals. PrPSc is the principal component of the transmissible neurotoxic prion agent. Site-directed mutagenesis was used to generate Drosophila transgenic for murine or hamster PrP (prion protein) that carry single-codon mutations associated with genetic human prion disease. Mouse or hamster PrP harbouring an FFI (D178N) or fCJD (E200K) mutation showed mild Proteinase K resistance when expressed in Drosophila Adult Drosophila transgenic for FFI or fCJD variants of mouse or hamster PrP displayed a spontaneous decline in locomotor ability that increased in severity as the flies aged. Significantly, this mutant PrP-mediated neurotoxic fly phenotype was transferable to recipient Drosophila that expressed the wild-type form of the transgene. Collectively, these novel data are indicative of the spontaneous formation of a PrP-dependent neurotoxic phenotype in FFI- or CJD-PrP transgenic Drosophila and show that inherited human prion disease can be modelled in this invertebrate host (Thackray, 2017).

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Polyglutamine (polyQ) disorders

Yadav, S. and Tapadia, M.G.
(2016). Expression of polyQ aggregates in Malpighian tubules leads to degeneration in Drosophila melanogaster. Dev Biol 409(1): 166-80. PubMed ID: 26517966

Abstract
Polyglutamine (polyQ) disorders are caused by expanded CAG (Glutamine) repeats in neurons in the brain. The expanded repeats are also expressed in the non-neuronal cells, however, their contribution to disease pathogenesis is not very well studied. This study expressed a stretch of 127 Glutamine repeats in Malpighian tubules (MTs) of Drosophila melanogaster as these tissues do not undergo ecdysone induced histolysis during larval to pupal transition at metamorphosis. Progressive degeneration, which is the hallmark of neurodegeneration was also observed in MTs. The mutant protein forms inclusion bodies in the nucleus resulting in expansion of the nucleus and affect chromatin organization which appear loose and open, eventually resulting in DNA fragmentation and blebbing. A virtual absence of tubule lumen was observed followed by functional abnormalities. As development progressed, severe abnormalities affecting pupal epithelial morphogenesis processes were observed resulting in complete lethality. Distribution of heterogeneous RNA binding protein (hnRNP), HRB87F, Wnt/wingless and JNK signaling and expression of Relish was also found to be affected. Expression of multi-drug resistance genes following polyQ expression was up regulated. The study gives an insight into the effects of polyQ aggregates in non-neuronal tissues (Yadav, 2016).

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Spinocerebellar ataxia

Tsou, W. L., Qiblawi, S. H., Hosking, R. R., Gomez, C. M. and Todi, S. V. (2016). Polyglutamine length-dependent toxicity from alpha1ACT in Drosophila models of spinocerebellar ataxia type 6. Biol Open 5(12): 1770-1775. PubMed ID: 27979829

Abstract

Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease that results from abnormal expansion of a polyglutamine (polyQ) repeat. SCA6 is caused by CAG triplet repeat expansion in the gene CACNA1A, resulting in a polyQ tract of 19-33 in patients. CACNA1A, a bicistronic gene, encodes the α1A calcium channel subunit and the transcription factor, alpha1ACT. PolyQ expansion in α1ACT causes degeneration in mice. The first Drosophila models of SCA6 have been described that express α1ACT with a normal (11Q) or hyper-expanded (70Q) polyQ. This study reports additional alpha1ACT transgenic flies, which express full-length α1ACT with a 33Q repeat. α1ACT33Q is toxic in Drosophila, but less so than the 70Q version. When expressed everywhere, α1ACT33Q-expressing adults die earlier than flies expressing the normal allele. α1ACT33Q causes retinal degeneration and leads to aggregated species in an age-dependent manner, but at a slower pace than the 70Q counterpart. According to western blots, α1ACT33Q localizes less readily in the nucleus than α1ACT70Q, providing clues into the importance of polyQ tract length on α1ACT localization and its site of toxicity. These new lines are expected to be highly valuable for future work on SCA6 (Tsou, 2016).

Wu, Y. L., Chang, J. C., Lin, W. Y., Li, C. C., Hsieh, M., Chen, H. W., Wang, T. S., Liu, C. S. and Liu, K. L. (2017). Treatment with caffeic acid and resveratrol alleviates oxidative stress induced neurotoxicity in cell and Drosophila models of Spinocerebellar ataxia type3. Sci Rep 7(1): 11641. PubMed ID: 28912527

Abstract

Spinocerebellar ataxia type 3 (SCA3) is caused by the expansion of a polyglutamine (polyQ) repeat in the protein ataxin-3 which is involved in susceptibility to mild oxidative stress induced neuronal death. This study shows that caffeic acid (CA) and resveratrol (Res) decreased reactive oxygen species (ROS), mutant ataxin-3 and apoptosis and increased autophagy in the pro-oxidant tert-butyl hydroperoxide (tBH)-treated SK-N-SH-MJD78 cells containing mutant ataxin-3. Furthermore, CA and Res improved survival and locomotor activity and decreased mutant ataxin-3 and ROS levels in tBH-treated SCA3 Drosophila. CA and Res also altered p53 and nuclear factor-kappaB (NF-kappaB) activation and expression in tBH-treated cell and fly models of SCA3, respectively. Blockade of NF-kappaB activation annulled the protective effects of CA and Res on apoptosis, ROS, and p53 activation in tBH-treated SK-N-SH-MJD78 cells, which suggests the importance of restoring NF-kappaB activity by CA and Res. These findings suggest that CA and Res may be useful in the management of oxidative stress induced neuronal apoptosis in SCA3 (Wu, 2017).

Avery, A. W., Thomas, D. D. and Hays, T. S. (2017). (2017). beta-III-spectrin spinocerebellar ataxia type 5 mutation reveals a dominant cytoskeletal mechanism that underlies dendritic arborization. Proc Natl Acad Sci U S A 114(44): E9376-e9385. PubMed ID: 29078305

Abstract

A spinocerebellar ataxia type 5 (SCA5) L253P mutation in the actin-binding domain (ABD) of beta-III-spectrin causes high-affinity actin binding and decreased thermal stability in vitro. This study shows in mammalian cells, at physiological temperature, that the mutant ABD retains high-affinity actin binding. Significantly, evidence is provided that the mutation alters the mobility and recruitment of beta-III-spectrin in mammalian cells, pointing to a potential disease mechanism. To explore this mechanism, a Drosophila SCA5 model was developed in which an equivalent mutant Drosophila beta-spectrin is expressed in neurons that extend complex dendritic arbors, such as Purkinje cells, targeted in SCA5 pathogenesis. The mutation causes a proximal shift in arborization coincident with decreased beta-spectrin localization in distal dendrites. SCA5 beta-spectrin dominantly mislocalizes alpha-spectrin and ankyrin-2, components of the endogenous spectrin cytoskeleton. These data suggest that high-affinity actin binding by SCA5 beta-spectrin interferes with spectrin-actin cytoskeleton dynamics, leading to a loss of a cytoskeletal mechanism in distal dendrites required for dendrite stabilization and arbor outgrowth (Avery, 2017).

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Retinitis pigmentosa

Chow, C. Y., Kelsey, K. J., Wolfner, M. F. and Clark, A. G.
(2015). Candidate genetic modifiers of retinitis pigmentosa identified by exploiting natural variation in Drosophila. Hum Mol Genet 25(4):651-9. PubMed ID: 26662796

Abstract
Individuals carrying the same pathogenic mutation can present with a broad range of disease outcomes. While some of this variation arises from environmental factors, it is increasingly recognized that the background genetic variation of each individual can have a profound effect on the expressivity of a pathogenic mutation. In order to understand this background effect on disease-causing mutations, studies need to be performed across a wide range of backgrounds. Recent advancements in model organism biology allow testing of mutations across genetically diverse backgrounds and identification of the genes that influence the expressivity of a mutation. This study used the Drosophila Genetic Reference Panel, a collection of approximately 200 wild-derived strains, to test the variability of the retinal phenotype of the Rh1G69D Drosophila model of retinitis pigmentosa (RP). The Rh1G69D retinal phenotype is quite a variable quantitative phenotype. To identify the genes driving this extensive phenotypic variation, a genome-wide association study was performed. One hundred and six candidate genes were identified, including 14 high-priority candidates. Functional testing by RNAi indicates that 10/13 top candidates tested influence the expressivity of Rh1G69D. The human orthologs of the candidate genes have not previously been implicated as RP modifiers and their functions are diverse, including roles in endoplasmic reticulum stress, apoptosis and retinal degeneration and development. This study demonstrates the utility of studying a pathogenic mutation across a wide range of genetic backgrounds. These candidate modifiers provide new avenues of inquiry that may reveal new RP disease mechanisms and therapies (Chow, 2015).

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Skin cancer and nucleotide excision repair

Yang, Y., He, S., Wang, Q., Li, F., Kwak, M. J., Chen, S., O'Connell, D., Zhang, T., Pirooz, S. D., Jeon, Y., Chimge, N. O., Frenkel, B., Choi, Y., Aldrovandi, G. M., Oh, B. H., Yuan, Z. and Liang, C.
(2016). Autophagic UVRAG promotes UV-induced photolesion repair by activation of the CRL4(DDB2) E3 ligase. Mol Cell 62: 507-519. PubMed ID: 27203177

Abstract

UV-induced DNA damage, a major risk factor for skin cancers, is primarily repaired by nucleotide excision repair (NER). UV radiation resistance-associated gene (UVRAG) is a tumor suppressor involved in autophagy. It was initially isolated as a cDNA partially complementing UV sensitivity in xeroderma pigmentosum (XP), but this was not explored further. This study shows that UVRAG plays an integral role in UV-induced DNA damage repair. It localizes to photolesions and associates with DDB1 to promote the assembly and activity of the DDB2-DDB1-Cul4A-Roc1 (CRL4(DDB2)) ubiquitin ligase complex, leading to efficient XPC recruitment and global genomic NER. UVRAG depletion decreased substrate handover to XPC and conferred UV-damage hypersensitivity. The importance of UVRAG for UV-damage tolerance was confirmed using a Drosophila model. Furthermore, increased UV-signature mutations in melanoma correlate with reduced expression of UVRAG. These results identify UVRAG as a regulator of CRL4(DDB2)-mediated NER and suggest that its expression levels may influence melanoma predisposition (Yang, 2016).

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Spinal muscular atrophy

Borg, R. M., Fenech Salerno, B., Vassallo, N., Bordonne, R. and Cauchi, R. J.
(2016). Disruption of snRNP biogenesis factors Tgs1 and pICln induces phenotypes that mirror aspects of SMN-Gemins complex perturbation in Drosophila, providing new insights into spinal muscular atrophy. Neurobiol Dis 94: 245-258. PubMed ID: 27388936

Abstract

The neuromuscular disorder, spinal muscular atrophy (SMA), results from insufficient levels of the survival motor neuron (SMN; see Drosophila Smn) protein. Together with Gemins 2-8 and Unrip, SMN forms the large macromolecular SMN-Gemins complex, which is known to be indispensable for chaperoning the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs). It remains unclear whether disruption of this function is responsible for the selective neuromuscular degeneration in SMA. This present study shows that loss of wing morphogenesis defect (wmd), the Drosophila Unrip orthologue, has a negative impact on the motor system. However, due to lack of a functional relationship between wmd/Unrip and Gemin3, it is likely that Unrip joined the SMN-Gemins complex only recently in evolution. Second, disruption of either Tgs1 or pICln, two cardinal players in snRNP biogenesis, results in viability and motor phenotypes that closely resemble those previously uncovered on loss of the constituent members of the SMN-Gemins complex. Interestingly, overexpression of both factors leads to motor dysfunction in Drosophila, a situation analogous to that of Gemin2. Toxicity is conserved in the yeast S. pombe where pICln overexpression induces a surplus of Sm proteins in the cytoplasm, indicating that a block in snRNP biogenesis is partly responsible for this phenotype. Importantly, this study shows a strong functional relationship and a physical interaction between Gemin3 and either Tgs1 or pICln. It is proposed that snRNP biogenesis is the pathway connecting the SMN-Gemins complex to a functional neuromuscular system, and its disturbance most likely leads to the motor dysfunction that is typical in SMA (Borg, 2016).

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Spinocerebellar Ataxia

Khare, S., et al.
(2017). A KCNC3 mutation causes a neurodevelopmental, non-progressive SCA13 subtype associated with dominant negative effects and aberrant EGFR trafficking. PLoS One 12(5): e0173565. PubMed ID: 28467418

Abstract

The autosomal dominant spinocerebellar ataxias (SCAs) are a diverse group of neurological disorders anchored by the phenotypes of motor incoordination and cerebellar atrophy. This study study focused on SCA13, which is caused by several allelic variants in the voltage-gated potassium channel KCNC3 (Kv3.3). The clinical phenotype of four SCA13 kindreds are detailed that confirm causation of the KCNC3R423H allele. The heralding features demonstrate congenital onset with non-progressive, neurodevelopmental cerebellar hypoplasia and lifetime improvement in motor and cognitive function that implicate compensatory neural mechanisms. Targeted expression of human KCNC3R423H in Drosophila triggers aberrant wing veins, maldeveloped eyes, and fused ommatidia consistent with the neurodevelopmental presentation of patients. Furthermore, human KCNC3R423H expression in mammalian cells results in altered glycosylation and aberrant retention of the channel in anterograde and/or endosomal vesicles. Confirmation of the absence of plasma membrane targeting was based on the loss of current conductance in cells expressing the mutant channel. Mechanistically, genetic studies in Drosophila, along with cellular and biophysical studies in mammalian systems, demonstrate the dominant negative effect exerted by the mutant on the wild-type (WT) protein, which explains dominant inheritance. Ocular co-expression of KCNC3R423H with Drosophila epidermal growth factor receptor (dEgfr) results in striking rescue of the eye phenotype, whereas KCNC3R423H expression in mammalian cells results in aberrant intracellular retention of human epidermal growth factor receptor (EGFR). Together, these results indicate that the neurodevelopmental consequences of KCNC3R423H may be mediated through indirect effects on EGFR signaling in the developing cerebellum. These results therefore confirm the KCNC3R423H allele as causative for SCA13, through a dominant negative effect on KCNC3WT and links with EGFR that account for dominant inheritance, congenital onset, and disease pathology (Khare, 2017).

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Squamous cell carcinoma

Fu, W., Sun, J., Huang, G., Liu, J. C., Kaufman, A., Ryan, R. J., Ramanathan, S. Y., Venkatesh, T. and Singh, B.
(2016). Squamous cell carcinoma related oncogene (SCCRO) family members regulate cell growth and proliferation through their cooperative and antagonistic effects on Cullin neddylation. J Biol Chem 291(12): 6200-17. PubMed ID: 26792857

Abstract
SCCRO (squamous cell carcinoma related oncogene; a.k.a. DCUN1D1) is a highly conserved gene that functions as an E3 in neddylation. Although inactivation of SCCRO in yeast results in lethality, SCCRO-/- mice are viable. The exclusive presence of highly conserved paralogues in higher organisms led to an assessment of whether compensation by SCCRO's paralogues rescues lethality in SCCRO-/- mice. Using murine and Drosophila models, the in vivo activities of SCCRO and its paralogues were assessed in cullin neddylation (see Drosophila Cullin1). SCCRO family members were found to have overlapping and antagonistic activity that regulates neddylation and cell proliferation activities in vivo. In flies, both dSCCRO (CG7427) and dSCCRO3 (CG13322) promote neddylation and cell proliferation, whereas dSCCRO4 (CG6597) negatively regulates these processes. Analysis of somatic clones showed that the effects that these paralogues have on proliferation serve to promote cell competition, leading to apoptosis in clones, with a net decrease in neddylation activity. dSCCRO and, to a lesser extent, dSCCRO3 rescue the neddylation and proliferation defects promoted by expression of SCCRO4. dSCCRO and dSCCRO3 functioned cooperatively, with their coexpression resulting in an increase in both the neddylated cullin fraction and proliferation activity. In contrast, human SCCRO and SCCRO4 promotes and human SCCRO3 inhibits neddylation and proliferation when expressed in flies. These findings provide the first insights into the mechanisms through which SCCRO family members cooperatively regulate neddylation and cell proliferation.

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Date revised: 22 January 2017

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