Monday, November 18, 2019

Drosophila study contributes to understanding molecular mechanisms related to Zika virus-associated microcephaly

Mutations in ANKLE2, a ZIKA Virus Target, Disrupt an Asymmetric Cell Division Pathway in Drosophila Neuroblasts to Cause Microcephaly

Nichole Link, Hyunglok Chung, Angad Jolly, Ghayda M. Mirzaa, James R. Lupski, Hugo J. Bellen
Published:November 14, 2019
DOI:https://doi.org/10.1016/j.devcel.2019.10.009

Summary: "The apical Par complex, which contains atypical protein kinase C (aPKC), Bazooka (Par-3), and Par-6, is required for establishing polarity during asymmetric division of neuroblasts in Drosophila, and its activity depends on L(2)gl. We show that loss of Ankle2, a protein associated with microcephaly in humans and known to interact with Zika protein NS4A, reduces brain volume in flies and impacts the function of the Par complex. Reducing Ankle2 levels disrupts endoplasmic reticulum (ER) and nuclear envelope morphology, releasing the kinase Ballchen-VRK1 into the cytosol. These defects are associated with reduced phosphorylation of aPKC, disruption of Par-complex localization, and spindle alignment defects. Importantly, removal of one copy of ballchen or l(2)gl suppresses Ankle2 mutant phenotypes and restores viability and brain size. Human mutational studies implicate the above-mentioned genes in microcephaly and motor neuron disease. We suggest that NS4A, ANKLE2, VRK1, and LLGL1 define a pathway impinging on asymmetric determinants of neural stem cell division."


Fly studies contribute to understanding of novel monogenic cause of steroid-resistance nephrotic syndrome

Kampf LL, Schneider R, Gerstner L, Thünauer R, Chen M, Helmstädter M, Amar A, Onuchic-Whitford AC, Loza Munarriz R, Berdeli A, Müller D, Schrezenmeier E, Budde K, Mane S, Laricchia KM, Rehm HL, MacArthur DG, Lifton RP, Walz G, Römer W, Bergmann C, Hildebrandt F, Hermle T. TBC1D8B Mutations Implicate RAB11-Dependent Vesicular Trafficking in the Pathogenesis of Nephrotic Syndrome. J Am Soc Nephrol. 2019 Nov 15. pii: ASN.2019040414. doi: 10.1681/ASN.2019040414. PMID: 31732614.

From the abstract: "Mutations in about 50 genes have been identified as monogenic causes of nephrotic syndrome, a frequent cause of CKD. ... We used whole-exome sequencing to identify novel monogenic causes of steroid-resistant nephrotic syndrome (SRNS). We analyzed the functional significance of an SRNS-associated gene in vitro and in podocyte-like Drosophila nephrocytes ..."

Monday, November 4, 2019

Experiments in Drosophila contribute to study of human gene variants associated with an early onset epileptic encephalopathy

Suzuki H, Yoshida T, Morisada N, Uehara T, Kosaki K, Sato K, Matsubara K, Takano-Shimizu T, Takenouchi T. De novo NSF mutations cause early infantile epileptic encephalopathy. Ann Clin Transl Neurol. 2019 Nov 1. doi: 10.1002/acn3.50917. PubMed PMID: 31675180.

Abstract: "N-ethylmaleimide-sensitive factor (NSF) plays a critical role in intracellular vesicle transport, which is essential for neurotransmitter release. Herein, we, for the first time, document human monogenic disease phenotype of de novo pathogenic variants in NSF, that is, epileptic encephalopathy of early infantile onset. When expressed in the developing eye of Drosophila, the mutant NSF severely affected eye development, while the wild-type allele had no detectable effect under the same conditions. Our findings suggest that the two pathogenic variants exert a dominant negative effect. De novo heterozygous mutations in the NSF gene cause early infantile epileptic encephalopathy."

Wednesday, October 30, 2019

Fly study related to distal hereditary motor neuropathy

Kang KH, Han JE, Hong YB, Nam SH, Choi BO, Koh H. Human HSPB1 mutation recapitulates features of distal hereditary motor neuropathy (dHMN) in Drosophila. Biochem Biophys Res Commun. 2019 Oct 17. pii: S0006-291X(19)32012-1. PubMed PMID: 31630804.

Abstract: "Distal hereditary motor neuropathies (dHMN) are a group of inherited peripheral nerve disorders characterized by length-dependent motor neuron weakness and subsequent muscle atrophy. Missense mutations in the gene encoding small heat shock protein HSPB1 (HSP27) have been associated with hereditary neuropathies including dHMN. HSPB1 is a member of the small heat shock protein (sHSP) family characterized by a highly conserved α-crystallin domain that is critical to their chaperone activity. In this study, we modeled HSPB1 mutant-induced neuropathies in Drosophila using a human HSPB1S135F mutant that has a missense mutation in its α-crystallin domain. Overexpression of the HSPB1 mutant produced no significant defect in the Drosophila development, however, a partial reduction in the life span was observed. Further, the HSPB1 mutant gene induced an obvious loss of motor activity when expressed in Drosophila neurons. Moreover, suppression of histone deacetylase 6 (HDAC6) expression, which has critical roles in HSPB1 mutant-induced axonal defects, successfully rescued the motor defects in the HSPB1 mutant Drosophila model."

Friday, October 11, 2019

Drosophila studies help identify and understand role of the CSDE1 gene in an autism-related syndrome

Guo H, Li Y, Shen L, Wang T, Jia X, Liu L, Xu T, Ou M, Hoekzema K, Wu H, et al. Disruptive variants of CSDE1 associate with autism and interfere with neuronal development and synaptic transmission. Sci Adv. 2019 Sep 25;5(9):eaax2166. PubMed PMID: 31579823; PubMed Central PMCID: PMC6760934.

Abstract: "RNA binding proteins are key players in posttranscriptional regulation and have been implicated in neurodevelopmental and neuropsychiatric disorders. Here, we report a significant burden of heterozygous, likely gene-disrupting variants in CSDE1 (encoding a highly constrained RNA binding protein) among patients with autism and related neurodevelopmental disabilities. Analysis of 17 patients identifies common phenotypes including autism, intellectual disability, language and motor delay, seizures, macrocephaly, and variable ocular abnormalities. HITS-CLIP revealed that Csde1-binding targets are enriched in autism-associated gene sets, especially FMRP targets, and in neuronal development and synaptic plasticity-related pathways. Csde1 knockdown in primary mouse cortical neurons leads to an overgrowth of the neurites and abnormal dendritic spine morphology/synapse formation and impaired synaptic transmission, whereas mutant and knockdown experiments in Drosophila result in defects in synapse growth and synaptic transmission. Our study defines a new autism-related syndrome and highlights the functional role of CSDE1 in synapse development and synaptic transmission."

Monday, October 7, 2019

New drug target for renal cancer identified based on fly and human studies--work from the lab of 2019 Nobel prize winner W. Kaelin

Nicholson HE, Tariq Z, Housden BE, Jennings RB, Stransky LA, Perrimon N, Signoretti S, Kaelin WG Jr. HIF-independent synthetic lethality between CDK4/6 inhibition and VHL loss across species. Sci Signal. 2019 Oct 1;12(601). PubMed PMID: 31575731.

Abstract: "Inactivation of the VHL tumor suppressor gene is the signature initiating event in clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, and causes the accumulation of hypoxia-inducible factor 2α (HIF-2α). HIF-2α inhibitors are effective in some ccRCC cases, but both de novo and acquired resistance have been observed in the laboratory and in the clinic. Here, we identified synthetic lethality between decreased activity of cyclin-dependent kinases 4 and 6 (CDK4/6) and VHL inactivation in two species (human and Drosophila) and across diverse human ccRCC cell lines in culture and xenografts. Although HIF-2α transcriptionally induced the CDK4/6 partner cyclin D1, HIF-2α was not required for the increased CDK4/6 requirement of VHL-/- ccRCC cells. Accordingly, the antiproliferative effects of CDK4/6 inhibition were synergistic with HIF-2α inhibition in HIF-2α-dependent VHL-/- ccRCC cells and not antagonistic with HIF-2α inhibition in HIF-2α-independent cells. These findings support testing CDK4/6 inhibitors as treatments for ccRCC, alone and in combination with HIF-2α inhibitors."

Review: "Insights from Drosophila melanogaster model of Alzheimer's disease"

Tue NT, Dat TQ, Ly LL, Anh VD, Yoshida H. Insights from Drosophila melanogaster model of Alzheimer's disease. Front Biosci (Landmark Ed). 2020 Jan 1;25:134-146. PubMed PMID: 31585881.

Abstract: "Alzheimer's disease (AD) is a common chronic neurodegenerative disease that mainly affects the medial temporal lobe and associated neocortical structures. The disease process involves two abnormal structures, plaques and tangles, which damage and destroy nerve cells. Tangles are twisted fibers of tau protein that build up inside cells. Plaques are deposits of a protein fragment called amyloid-beta (Aβ) that accumulate in the spaces between nerve cells. Aβ derives from the amyloid precursor protein and is the main component of amyloid plaques in the AD brain. Although AD has been extensively examined, its pathogenetic mechanisms remain unclear and there are currently no effective drugs for this disorder. Many AD model systems have recently been established using Drosophila melanogaster by expressing the proteins involved in AD in the brain. These systems successfully reflect some of the symptoms associated with AD such as the onset of learning defects, age-dependent short-term memory impairment, increase of wakefulness and consolidated sleep disruption by expressing human Aβ42 or human APP/BACE in Drosophila central nervous system. We herein discuss these Drosophila AD models."