Friday, May 18, 2018

New fly model of Essential Tremor

Smith P, Arias R, Sonti S, Odgerel Z, Santa-Maria I, McCabe BD, Tsaneva-Atanasova K, Louis ED, Hodge JJL, Clark LN. A Drosophila Model of Essential Tremor. Sci Rep. 2018 May 16;8(1):7664. PMID: 29769701.

The abstract: "Essential Tremor (ET) is one of the most common neurological diseases, with an estimated 7 million affected individuals in the US; the pathophysiology of the disorder is poorly understood. Recently, we identified a mutation (KCNS2 (Kv9.2), c.1137 T > A, p.(D379E) in an electrically silent voltage-gated K+ channel α-subunit, Kv9.2, in a family with ET, that modulates the activity of Kv2 channels. We have produced transgenic Drosophila lines that express either the human wild type Kv9.2 (hKv9.2) or the ET causing mutant Kv9.2 (hKv9.2-D379E) subunit in all neurons. We show that the hKv9.2 subunit modulates activity of endogenous Drosophila K+ channel Shab. The mutant hKv9.2-D379E subunit showed significantly higher levels of Shab inactivation and a higher frequency of spontaneous firing rate consistent with neuronal hyperexcitibility. We also observed behavioral manifestations of nervous system dysfunction including effects on night time activity and sleep. This functional data further supports the pathogenicity of the KCNS2 (p.D379E) mutation, consistent with our prior observations including co-segregation with ET in a family, a likely pathogenic change in the channel pore domain and absence from population databases. The Drosophila hKv9.2 transgenic model recapitulates several features of ET and may be employed to advance our understanding of ET disease pathogenesis."

Fly model of neurodegeneration used in study of glycation

Vicente Miranda H, Gomes MA, Branco-Santos J, Breda C, Lázaro DF, Lopes LV, Herrera F, Giorgini F, Outeiro TF. Glycation potentiates neurodegeneration in models of Huntington's disease. Sci Rep. 2016 Nov 18;6:36798. PMID: 27857176; PMCID: PMC5114697.

From the abstract: "Protein glycation is an age-dependent posttranslational modification associated with several neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. By modifying amino-groups, glycation interferes with folding of proteins, increasing their aggregation potential. Here, we studied the effect of pharmacological and genetic manipulation of glycation on huntingtin (HTT), the causative protein in Huntington's disease (HD). ... increased glycation enhanced HTT toxicity in human cells and neurodegeneration in fruit flies, impairing eclosion and decreasing life span. Overall, our study provides evidence that glycation modulates HTT exon-1 aggregation and toxicity ...."

Thursday, May 17, 2018

Fly model of Alzheimer's disease to test a potential therapeutic treatment

Beg T, Jyoti S, Naz F, Rahul, Ali F, Ali SK, Reyad AM, Siddique YH. Protective effect of kaempferol on the transgenic Drosophila model of Alzheimer's disease. CNS Neurol Disord Drug Targets. 2018 May 8. PMID: 29745345.

From the abstract: "Alzheimer's disease (AD) is characterized by the accumulation and deposition of β-amyloid peptides leading to a progressive neuronal damage and cell loss. Besides several hypotheses for explaining the neurodegenerative mechanisms, oxidative stress has been considered to be one of them. Till date, there is no cure for AD, but the pathogenesis of the disease could be delayed by the use of natural antioxidants. In this context, we decided to study the effect of kaempferol against the transgenic Drosophila expressing human Aβ-42. ...The AD flies were allowed to feed on the diet having 10, 20, 30 and 40µM of kaempferol for 30 days. After 30 days of exposure, the Aβ-flies were studied ... The results of the present study reveal that the exposure of AD flies to kaempferol delayed the loss of climbing ability, memory, reduced the oxidative stress and acetylcholinesterase activity."

Context matters: results of fly studies suggests contribution of "deleterious heteromosaicism" to disease

Akiyama T, User SD, Gibson MC. Somatic clones heterozygous for recessive disease alleles of BMPR1A exhibit unexpected phenotypes in Drosophila. Elife. 2018 May 10;7. PMID: 29745898.

The abstract: "The majority of mutations studied in animal models are designated as recessive based on the absence of visible phenotypes in germline heterozygotes. Accordingly, genetic studies primarily rely on homozygous loss-of-function to determine gene requirements, and a conceptually-related 'two-hit model' remains the central paradigm in cancer genetics. Here we investigate pathogenesis due to somatic mutation in epithelial tissues, a process that predominantly generates heterozygous cell clones. To study somatic mutation in Drosophila, we generated inducible alleles that mimic human Juvenile polyposis-associated BMPR1A mutations. Unexpectedly, four of these mutations had no phenotype in heterozygous carriers but exhibited clear tissue-level effects when present in somatic clones of heterozygous cells. We conclude that these alleles are indeed recessive when present in the germline, but nevertheless deleterious when present in heterozygous clones. This unforeseen effect, deleteriousheteromosaicism, suggests a 'one-hit' mechanism for disease initiation that may explain some instances of pathogenesis associated with spontaneous mutation."

Review of Drosophila research related to ALS

Zhang K, Coyne AN, Lloyd TE. Drosophila models of amyotrophic lateral sclerosis with defects in RNA metabolism. Brain Res. 2018 May 9. PMID: 29752901.

From the abstract: " ... The conservation of nervous system biology coupled with the rapid life cycle and powerful genetic tools in the fly have enabled the identification of novel therapeutic targets that have been validated in vertebrate model systems and human patients. A recent example is in the study of the devastating motor neuron degenerative disease amyotrophic lateral sclerosis (ALS). ... In this review, we will discuss the utilization of Drosophila models of ALS with defects in RNA metabolism."


Study of a fly model of fragile X-syndrome suggests "a potentially general mechanism for intellectual disability"

Franco LM, Okray Z, Linneweber GA, Hassan BA, Yaksi E. Reduced Lateral Inhibition Impairs Olfactory Computations and Behaviors in a Drosophila Model of Fragile X Syndrome. Curr Biol. 2017 Apr 24;27(8):1111-1123. PMID: 28366741; PMCID: PMC5405172.

From the abstract: "Fragile X syndrome (FXS) patients present neuronal alterations that lead to severe intellectual disability, but the underlying neuronal circuit mechanisms are poorly understood. An emerging hypothesis postulates that reduced GABAergic inhibition of excitatory neurons is a key component in the pathophysiology of FXS. Here, we directly test this idea in a FXS Drosophila model. ... We provide direct evidence that deficient inhibition impairs sensory computations and behavior in an in vivo model of FXS. Together with evidence of impaired inhibition in autism and Rett syndrome, these findings suggest a potentially general mechanism for intellectual disability."

Also appearing recently, this review:

Drozd M, Bardoni B, Capovilla M. Modeling Fragile X Syndrome in Drosophila. Front Mol Neurosci. 2018 Apr 16;11:124. doi: 10.3389/fnmol.2018.00124. PMID: 29713264; PMCID: PMC5911982.

Fly studies help shed light on contribution of KAT2B variants to ADD3-associated disorders

Gonçalves S, Patat J, Guida MC, Lachaussée N, Arrondel C, Helmstädter M, Boyer O, Gribouval O, Gubler MC, Mollet G, Rio M, Charbit M, Bole-Feysot C, Nitschke P, Huber TB, Wheeler PG, Haynes D, Juusola J, Billette de Villemeur T, Nava C, Afenjar A, Keren B, Bodmer R, Antignac C, Simons M. A homozygous KAT2B variant modulates the clinical phenotype of ADD3 deficiency in humans and flies. PLoS Genet. 2018 May 16;14(5):e1007386. PMID: 29768408.

The abstract: "Recent evidence suggests that the presence of more than one pathogenic mutation in a single patient is more common than previously anticipated. One of the challenges hereby is to dissect the contribution of each gene mutation, for which animal models such as Drosophila can provide a valuable aid. Here, we identified three families with mutations in ADD3, encoding for adducin-γ, with intellectual disability, microcephaly, cataracts and skeletal defects. In one of the families with additional cardiomyopathy and steroid-resistant nephrotic syndrome (SRNS), we found a homozygous variant in KAT2B, encoding the lysine acetyltransferase 2B, with impact on KAT2B protein levels in patient fibroblasts, suggesting that this second mutation might contribute to the increased disease spectrum. In order to define the contribution of ADD3 and KAT2B mutations for the patient phenotype, we performed functional experiments in the Drosophila model. We found that both mutations were unable to fully rescue the viability of the respective null mutants of the Drosophila homologs, hts and Gcn5, suggesting that they are indeed pathogenic in flies. While the KAT2B/Gcn5 mutation additionally showed a significantly reduced ability to rescue morphological and functional defects of cardiomyocytes and nephrocytes (podocyte-like cells), this was not the case for the ADD3 mutant rescue. Yet, the simultaneous knockdown of KAT2B and ADD3 synergistically impaired kidney and heart function in flies as well as the adhesion and migration capacity of cultured human podocytes, indicating that mutations in both genes may be required for the full clinical manifestation. Altogether, our studies describe the expansion of the phenotypic spectrum in ADD3 deficiency associated with a homozygous likely pathogenic KAT2B variant and thereby identify KAT2B as a susceptibility gene for kidney and heart disease in ADD3-associated disorders."