Tuesday, May 28, 2019

Drosophila study identifies genes relevant to consumption of drugs of abuse

Highfill CA, Baker BM, Stevens SD, Anholt RRH, Mackay TFC. Genetics of cocaine and methamphetamine consumption and preference in Drosophila melanogaster. PLoS Genet. 2019 May 20;15(5):e1007834. PMID: 31107875.

From the abstract: "Illicit use of psychostimulants, such as cocaine and methamphetamine, constitutes a significant public health problem. ... genetic factors that account for individual variation in susceptibility to substance abuse and addiction remain largely unknown. Drosophila melanogaster can serve as a translational model for studies on substance abuse, since flies have a dopamine transporter that can bind cocaine and methamphetamine, and exposure to these compounds elicits effects similar to those observed in people, suggesting conserved evolutionary mechanisms underlying drug responses. Here, we used the D. melanogaster Genetic Reference Panel to investigate the genetic basis for variation in psychostimulant drug consumption ... Quantification of natural genetic variation in voluntary consumption, preference, and change in consumption and preference over time for cocaine and methamphetamine uncovered significant genetic variation for all traits, including sex-, exposure- and drug-specific genetic variation. Genome wide association analyses identified both shared and drug-specific candidate genes ... "

Friday, May 24, 2019

Fly studies help provide insights into role of nucleocytoplasmic transport in ALS/FTD

Chou CC, Zhang Y, Umoh ME, Vaughan SW, Lorenzini I, Liu F, Sayegh M, Donlin-Asp PG, Chen YH, Duong DM, Seyfried NT, Powers MA, Kukar T, Hales CM, Gearing M, Cairns NJ, Boylan KB, Dickson DW, Rademakers R, Zhang YJ, Petrucelli L, Sattler R, Zarnescu DC, Glass JD, Rossoll W. TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD. Nat Neurosci. 2018 Feb;21(2):228-239. doi: 10.1038/s41593-017-0047-3. Epub 2018 Jan 8. PubMed PMID: 29311743; PubMed Central PMCID: PMC5800968.

Abstract: "The cytoplasmic mislocalization and aggregation of TAR DNA-binding protein-43 (TDP-43) is a common histopathological hallmark of the amyotrophic lateral sclerosis and frontotemporal dementia disease spectrum (ALS/FTD). However, the composition of aggregates and their contribution to the disease process remain unknown. Here we used proximity-dependent biotin identification (BioID) to interrogate the interactome of detergent-insoluble TDP-43 aggregates and found them enriched for components of the nuclear pore complex and nucleocytoplasmic transport machinery. Aggregated and disease-linked mutant TDP-43 triggered the sequestration and/or mislocalization of nucleoporins and transport factors, and interfered with nuclear protein import and RNA export in mouse primary cortical neurons, human fibroblasts and induced pluripotent stem cell-derived neurons. Nuclear pore pathology is present in brain tissue in cases of sporadic ALS and those involving genetic mutations in TARDBP and C9orf72. Our data strongly implicate TDP-43-mediated nucleocytoplasmic transport defects as a common disease mechanism in ALS/FTD."

See also comment in Nature Neuroscience.

How to lurk: Droosphila used in study related to attachment of the cholera-causing bacteria Vibrio cholerae to arthropod intestines

Kamareddine L, Wong ACN, Vanhove AS, Hang S, Purdy AE, Kierek-Pearson K, Asara JM, Ali A, Morris JG Jr, Watnick PI. Activation of Vibrio cholerae quorum sensing promotes survival of an arthropod host. Nat Microbiol. 2018 Feb;3(2):243-252. PMID: 29180725; PMCID: PMC6260827.

Abstract: "Vibrio cholerae colonizes the human terminal ileum to cause cholera, and the arthropod intestine and exoskeleton to persist in the aquatic environment. Attachment to these surfaces is regulated by the bacterial quorum-sensing signal transduction cascade, which allows bacteria to assess the density of microbial neighbours. Intestinal colonization with V. cholerae results in expenditure of host lipid stores in the model arthropod Drosophila melanogaster. Here we report that activation of quorum sensing in the Drosophila intestine retards this process by repressing V. cholerae succinate uptake. Increased host access to intestinal succinate mitigates infection-induced lipid wasting to extend survival of V. cholerae-infected flies. Therefore, quorum sensing promotes a more favourable interaction between V. cholerae and an arthropod host by reducing the nutritional burden of intestinal colonization."

Asking yourself, "Um, what?" Here's an interpretation by your blog author: 
Bacteria called Vibrio cholerae cause cholera in humans. When they're not doing that, they lurk inside the guts (and on the outsides) of arthropods that live in the water. This study uses fruit flies as a lab-friendly system in which to look at a specific aspect of the interaction between a host arthropod's gut and Vibrio bacteria. Turns out that confusing the bacteria about how many of themselves are around stops them from taking up a molecule called succinate, leaving more of the succinate around for the fly. With more succinate available, the fly uses up less of its fat reserves than it usually would when infected. This helps the infected fly survive longer.

Personalized platform that includes a complex fly genetic model used to identify a treatment strategy for a specific patient

A personalized platform identifies trametinib plus zoledronate for a patient with KRAS-mutant metastatic colorectal cancer.

Erdem Bangi1,*, Celina Ang2,3, Peter Smibert1,†, Andrew V. Uzilov4,5, Alexander G. Teague1, Yevgeniy Antipin4,5, Rong Chen4,5, Chana Hecht1, Nelson Gruszczynski1,‡, Wesley J. Yon1, Denis Malyshev1, Denise Laspina1, Isaiah Selkridge2, Hope Rainey2, Aye S. Moe4,5, Chun Yee Lau4,5, Patricia Taik4,5, Eric Wilck6, Aarti Bhardwaj2, Max Sung2,3, Sara Kim7, Kendra Yum7, Robert Sebra4,5, Michael Donovan3,8, Krzysztof Misiukiewicz2,3, Eric E. Schadt4,5,3, Marshall R. Posner2,3 and Ross L. Cagan1,3,§

1Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
2Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
3Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
4Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
5SEMA4, a Mount Sinai Venture, 333 Ludlow Street, South Tower, 3rd floor, Stamford, CT 06902, USA.
6Department of Radiology, The Mount Sinai Hospital, New York, NY 10029, USA.
7Department of Pharmacy, The Mount Sinai Hospital, New York, NY 10029, USA.
8Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Abstract: "Colorectal cancer remains a leading source of cancer mortality worldwide. Initial response is often followed by emergent resistance that is poorly responsive to targeted therapies, reflecting currently undruggable cancer drivers such as KRAS and overall genomic complexity. Here, we report a novel approach to developing a personalized therapy for a patient with treatment-resistant metastatic KRAS-mutant colorectal cancer. An extensive genomic analysis of the tumor’s genomic landscape identified nine key drivers. A transgenic model that altered orthologs of these nine genes in the Drosophila hindgut was developed; a robotics-based screen using this platform identified trametinib plus zoledronate as a candidate treatment combination. Treating the patient led to a significant response: Target and nontarget lesions displayed a strong partial response and remained stable for 11 months. By addressing a disease’s genomic complexity, this personalized approach may provide an alternative treatment option for recalcitrant disease such as KRAS-mutant colorectal cancer."

Read the article at Science Advances.
See also, coverage of the story in The Scientist.

Sunday, May 12, 2019