Wednesday, June 20, 2018

Genetic modifiers of neurodegeneration

Early online from Genetics:

Genetic Modifiers of Neurodegeneration in a Drosophila Model of Parkinson's Disease
Sierra Lavoy, Vinita G. Chittoor-Vinod, Clement Y. Chow and Ian Martin

From the abstract: "... There is increasing evidence that background genetic variation is a strong driver of disease variability ... To understand the genotype-phenotype relationship ... a large number of backgrounds must be studied. This can be efficiently achieved using model organism collections such as the Drosophila Genetic Reference Panel (DGRP). Here, we used the DGRP to assess the variability of locomotor dysfunction in a LRRK2 G2019S Drosophila melanogaster model of Parkinson's disease. We find substantial variability in the LRRK2 G2019S locomotor phenotype in different DGRP backgrounds. A genome-wide association study for candidate genetic modifiers reveals 177 genes that drive wide phenotypic variation, including 19 top association genes. Genes involved in the outgrowth and regulation of neuronal projections are enriched in these candidate modifiers. RNAi functional testing of the top association and neuronal projection-related genes reveals that pros, pbl, ct and CG33506 significantly modify age-related dopamine neuron loss and associated locomotor dysfunction in the Drosophila LRRK2 G2019S model. These results demonstrate how natural genetic variation can be used as a powerful tool to identify genes that modify disease-related phenotypes. ..."

Monday, June 4, 2018

Fly model contributes to understanding of spinocerebellar ataxia type 1

Bondar VV, Adamski CJ, Onur TS, Tan Q, Wang L, Diaz-Garcia J, Park J, Orr HT, Botas J, Zoghbi HY. PAK1 regulates ATXN1 levels providing an opportunity to modify its toxicity in Spinocerebellar ataxia type 1. Hum Mol Genet. 2018 May 30. PMID: 29860311.

The abstract: "Spinocerebellar ataxia type 1 (SCA1) is caused by the expansion of a trinucleotide repeat that encodes a polyglutamine tract in ataxin-1 (ATXN1). The expanded polygultamine in ATXN1 increases the protein's stability and results in its accumulation and toxicity. Previous studies have demonstrated that decreasing ATXN1 levels ameliorates SCA1 phenotypes and pathology in mouse models. We rationalized that reducing ATXN1 levels through pharmacological inhibition of its modulators could provide a therapeutic avenue for SCA1. Here, through a forward genetic screen in Drosophila we identified, p21-activated kinase 3 (Pak3) as a modulator of ATXN1 levels. Loss-of-function of fly Pak3 and Pak1, whose mammalian homologs are Group I of PAKs, reduces ATXN1 levels, and accordingly, improves disease pathology in a Drosophila model of SCA1. Knockdown of PAK1 potently reduces ATXN1 levels in mammalian cells independent of the well-characterized S776 phosphorylation site (known to stabilize ATXN1) thus revealing a novel molecular pathway that regulates ATXN1 levels. Furthermore, pharmacological inhibition of PAKs decreases ATXN1 levels in a mouse model of SCA1. To explore the potential of using PAK inhibitors in combination therapy, we combined the pharmacological inhibition of PAK with MSK1, a previously identified modulator of ATXN1, and examined their effects on ATXN1 levels. We found that inhibition of both pathways results in an additive decrease in ATXN1 levels. Together, this study identifies PAK signaling as a distinct molecular pathway that regulates ATXN1 levels and presents a promising opportunity to pursue for developing potential therapeutics for SCA1."

Review of fly models of Friedreich's Ataxia

Calap-Quintana P, Navarro JA, González-Fernández J, Martínez-Sebastián MJ, Moltó MD, Llorens JV. Drosophila melanogaster Models of Friedreich's Ataxia. Biomed Res Int. 2018 Apr 5;2018:5065190. PMID: 29850527; PMCID: PMC5907503.

From the abstract: "Friedreich's ataxia (FRDA) is a rare inherited recessive disorder affecting the central and peripheral nervous systems and other extraneural organs such as the heart and pancreas. This incapacitating condition usually manifests in childhood or adolescence, exhibits an irreversible progression that confines the patient to a wheelchair, and leads to early death. FRDA is caused by a reduced level of the nuclear-encoded mitochondrial protein frataxin due to an abnormal GAA triplet repeat expansion in the first intron of the human FXN gene. FXN is evolutionarily conserved, with orthologs in essentially all eukaryotes and some prokaryotes, leading to the development of experimental models of this disease in different organisms. These FRDA models have contributed substantially to our current knowledge of frataxin function and the pathogenesis of the disease, as well as to explorations of suitable treatments. Drosophila melanogaster, an organism that is easy to manipulate genetically, has also become important in FRDA research. This review describes the substantial contribution of Drosophila to FRDA research ..."

Thursday, May 31, 2018

FlyRNAi: in vivo fly RNAi screen identifies ortholog of SPO...

FlyRNAi: in vivo fly RNAi screen identifies ortholog of SPO...: Rossi F, Molnar C, Hashiyama K, Heinen JP, Pampalona J, Llamazares S, Reina J, Hashiyama T, Rai M, Pollarolo G, Fernández-Hernández I, Gonza...

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."