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Drosophila human disease

Ryszard Rzepecki, Yosef Gruenbaum
Lamins are evolutionarily conserved nuclear intermediate filament proteins. They provide structural support for the nucleus and help regulate many other nuclear activities. Mutations in human lamin genes, and especially in the LMNA gene, cause numerous diseases, termed laminopathies, including muscle, cardiac, metabolic, neuronal and early aging diseases. Most laminopathies arise from autosomal dominant missense mutations. Many of the mutant residues are conserved in the lamin genes of the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster...
March 20, 2018: Nucleus
Marta Zamarbide, Adam W Oaks, Heather L Pond, Julia S Adelman, M Chiara Manzini
Hundreds of genes are mutated in non-syndromic intellectual disability (ID) and autism spectrum disorder (ASD), with each gene often involved in only a handful of cases. Such heterogeneity can be daunting, but rare recessive loss of function (LOF) mutations can be a good starting point to provide insight into the mechanisms of neurodevelopmental disease. Biallelic LOF mutations in the signaling scaffold CC2D1A cause a rare form of autosomal recessive ID, sometimes associated with ASD and seizures. In parallel, we recently reported that Cc2d1a -deficient mice present with cognitive and social deficits, hyperactivity and anxiety...
2018: Frontiers in Genetics
Karolina Pierzynowska, Lidia Gaffke, Zuzanna Cyske, Michał Puchalski, Estera Rintz, Michał Bartkowski, Marta Osiadły, Michał Pierzynowski, Jagoda Mantej, Ewa Piotrowska, Grzegorz Węgrzyn
Autophagy is a process of degradation of macromolecules in the cytoplasm, particularly proteins of a long half-life, as well as whole organelles, in eukaryotic cells. Lysosomes play crucial roles during this degradation. Autophagy is a phylogenetically old, and evolutionarily conserved phenomenon which occurs in all eukaryotic cells. It can be found in yeast Saccharomyces cerevisiae, insect Drosophila melanogaster, and mammals, including humans. Its high importance for cell physiology has been recognized, and in fact, dysfunctions causing impaired autophagy are associated with many severe disorders, including cancer and metabolic brain diseases...
March 14, 2018: Metabolic Brain Disease
Juanjuan Zhao, Mathilda T M Mommersteeg
The Slit ligands and their Robo receptors are well-known for their roles during axon guidance in the central nervous system, but are still relatively unknown in the cardiac field. However, data from different animal models suggest a broad involvement of the pathway in many aspects of heart development, from cardiac cell migration and alignment, lumen formation, chamber formation, to the formation of the ventricular septum, semilunar and atrioventricular valves, caval veins and pericardium. Absence of one or more of the genes in the pathway results in defects ranging from bicuspid aortic valves to ventricular septal defects and abnormal venous connections to the heart...
March 10, 2018: Cardiovascular Research
Yukie Kushimura, Takahiko Tokuda, Yumiko Azuma, Itaru Yamamoto, Ikuko Mizuta, Toshiki Mizuno, Masanori Nakagawa, Morio Ueyama, Yoshitaka Nagai, Hideki Yoshida, Masamitsu Yamaguchi
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease characterized by the motor neuron degeneration that eventually leads to complete paralysis and death within 2-5 years after disease onset. One of the major pathological hallmark of ALS is abnormal accumulation of inclusions containing TAR DNA-binding protein-43 (TDP-43). TDP-43 is normally found in the nucleus, but in ALS, it localizes in the cytoplasm as inclusions as well as in the nucleus. Loss of nuclear TDP-43 functions likely contributes to neurodegeneration...
2018: American Journal of Neurodegenerative Disease
Marissa Cabay, Jasmine Harris, Scott A Shippy
The fruit fly is a frequently used model system with a high degree of human disease-related genetic homology. The quantitative chemical analysis of fruit fly tissues and hemolymph uniquely brings chemical signaling and compositional information to fly experimentation. The work here explores the impact of measured chemical content of hemolymph with three aspects of sample collection and preparation. Cellular content of hemolymph was quantitated and removed to determine hemolymph composition changes for seven primary amine analytes...
March 9, 2018: Analytical Chemistry
Laura Palanker Musselman, Ronald P Kühnlein
Excess adipose fat accumulation, or obesity, is a growing problem worldwide in terms of both the rate of incidence and the severity of obesity-associated metabolic disease. Adipose tissue evolved in animals as a specialized dynamic lipid storage depot: adipose cells synthesize fat (a process called lipogenesis) when energy is plentiful and mobilize stored fat (a process called lipolysis) when energy is needed. When a disruption of lipid homeostasis favors increased fat synthesis and storage with little turnover owing to genetic predisposition, overnutrition or sedentary living, complications such as diabetes and cardiovascular disease are more likely to arise...
March 7, 2018: Journal of Experimental Biology
Li Dong, Matteo Cornaglia, Gopalan Krishnamani, Jingwei Zhang, Laurent Mouchiroud, Thomas Lehnert, Johan Auwerx, Martin A M Gijs
The nematode Caenorhabditis elegans is an important model organism for biomedical research and genetic studies relevant to human biology and disease. Such studies are often based on high-resolution imaging of dynamic biological processes in the worm body tissues, requiring well-immobilized and physiologically active animals in order to avoid movement-related artifacts and to obtain meaningful biological information. However, existing immobilization methods employ the application of either anesthetics or servere physical constraints, by using glue or specific microfluidic on-chip mechanical structures, which in some cases may strongly affect physiological processes of the animals...
2018: PloS One
Marie E Oskarsson, Erik Hermansson, Ye Wang, Nils Welsh, Jenny Presto, Jan Johansson, Gunilla T Westermark
Aggregation of islet amyloid polypeptide (IAPP) into amyloid fibrils in islets of Langerhans is associated with type 2 diabetes, and formation of toxic IAPP species is believed to contribute to the loss of insulin-producing beta cells. The BRICHOS domain of integral membrane protein 2B (Bri2), a transmembrane protein expressed in several peripheral tissues and in the brain, has recently been shown to prevent fibril formation and toxicity of Aβ42, an amyloid-forming peptide in Alzheimer disease. In this study, we demonstrate expression of Bri2 in human islets and in the human beta-cell line EndoC-βH1...
March 5, 2018: Proceedings of the National Academy of Sciences of the United States of America
Carin A Loewen, Barry Ganetzky
Proper mitochondrial activity depends upon proteins encoded by genes in the nuclear and mitochondrial genomes that must interact functionally and physically in a precisely coordinated manner. Consequently, mito-nuclear allelic interactions are thought to be of crucial importance on an evolutionary scale, as well as for manifestation of essential biological phenotypes, including those directly relevant to human disease. Nonetheless, detailed molecular understanding of mito-nuclear interactions is still lacking, and definitive examples of such interactions in vivo are sparse...
March 1, 2018: Genetics
Sumaira Zamurrad, Hayden A M Hatch, Coralie Drelon, Helen M Belalcazar, Julie Secombe
Mutations in KDM5 family histone demethylases cause intellectual disability in humans. However, the molecular mechanisms linking KDM5-regulated transcription and cognition remain unknown. Here, we establish Drosophila as a model to understand this connection by generating a fly strain harboring an allele analogous to a disease-causing missense mutation in human KDM5C (kdm5A512P ). Transcriptome analysis of kdm5A512P flies revealed a striking downregulation of genes required for ribosomal assembly and function and a concomitant reduction in translation...
February 27, 2018: Cell Reports
Monika Oláhová, Wan Hee Yoon, Kyle Thompson, Sharayu Jangam, Liliana Fernandez, Jean M Davidson, Jennifer E Kyle, Megan E Grove, Dianna G Fisk, Jennefer N Kohler, Matthew Holmes, Annika M Dries, Yong Huang, Chunli Zhao, Kévin Contrepois, Zachary Zappala, Laure Frésard, Daryl Waggott, Erika M Zink, Young-Mo Kim, Heino M Heyman, Kelly G Stratton, Bobbie-Jo M Webb-Robertson, Michael Snyder, Jason D Merker, Stephen B Montgomery, Paul G Fisher, René G Feichtinger, Johannes A Mayr, Julie Hall, Ines A Barbosa, Michael A Simpson, Charu Deshpande, Katrina M Waters, David M Koeller, Thomas O Metz, Andrew A Morris, Susan Schelley, Tina Cowan, Marisa W Friederich, Robert McFarland, Johan L K Van Hove, Gregory M Enns, Shinya Yamamoto, Euan A Ashley, Michael F Wangler, Robert W Taylor, Hugo J Bellen, Jonathan A Bernstein, Matthew T Wheeler
ATP synthase, H+ transporting, mitochondrial F1 complex, δ subunit (ATP5F1D; formerly ATP5D) is a subunit of mitochondrial ATP synthase and plays an important role in coupling proton translocation and ATP production. Here, we describe two individuals, each with homozygous missense variants in ATP5F1D, who presented with episodic lethargy, metabolic acidosis, 3-methylglutaconic aciduria, and hyperammonemia. Subject 1, homozygous for c.245C>T (p.Pro82Leu), presented with recurrent metabolic decompensation starting in the neonatal period, and subject 2, homozygous for c...
February 16, 2018: American Journal of Human Genetics
Emily Reed, Svetlana Lutsenko, Oliver Bandmann
Wilson disease (WD) is an autosomal recessive disorder of copper metabolism manifesting with hepatic, neurological and psychiatric symptoms. The limitations of the currently available therapy for WD (particularly in the management of neuropsychiatric disease), together with our limited understanding of key aspects of this illness (e.g. neurological vs hepatic presentation) justify the ongoing need to study WD in suitable animal models. Four animal models of WD have been established: the Long-Evans Cinnamon rat, the toxic-milk mouse, the Atp7b knockout mouse and the Labrador retriever...
February 23, 2018: Journal of Neurochemistry
Gautam Pareek, Ruth E Thomas, Leo J Pallanck
The progressive accumulation of dysfunctional mitochondria is implicated in aging and in common diseases of the elderly. To oppose this occurrence, organisms employ a variety of strategies, including the selective degradation of oxidatively damaged and misfolded mitochondrial proteins. Genetic studies in yeast indicate that the ATPase Associated with diverse cellular Activities (AAA+ ) family of mitochondrial proteases account for a substantial fraction of this protein degradation, but their metazoan counterparts have been little studied, despite the fact that mutations in the genes encoding these proteases cause a variety of human diseases...
February 21, 2018: Cell Death & Disease
Pei-I Tsai, Chin-Hsien Lin, Chung-Han Hsieh, Amanda M Papakyrikos, Min Joo Kim, Valerio Napolioni, Carmen Schoor, Julien Couthouis, Ruey-Meei Wu, Zbigniew K Wszolek, Dominic Winter, Michael D Greicius, Owen A Ross, Xinnan Wang
Mitochondrial crista structure partitions vital cellular reactions and is precisely regulated by diverse cellular signals. Here, we show that, in Drosophila, mitochondrial cristae undergo dynamic remodeling among distinct subcellular regions and the Parkinson's disease (PD)-linked Ser/Thr kinase PINK1 participates in their regulation. Mitochondria increase crista junctions and numbers in selective subcellular areas, and this remodeling requires PINK1 to phosphorylate the inner mitochondrial membrane protein MIC60/mitofilin, which stabilizes MIC60 oligomerization...
February 14, 2018: Molecular Cell
Konstantin G Iliadi, Oxana B Gluscencova, Natalia Iliadi, Gabrielle L Boulianne
Infantile neuroaxonal dystrophy (INAD) is a fatal neurodegenerative disorder that typically begins within the first few years of life and leads to progressive impairment of movement and cognition. Several years ago, it was shown that >80% of patients with INAD have mutations in the phospholipase gene, PLA2G6. Interestingly, mutations in PLA2G6 are also causative in two other related neurodegenerative diseases, atypical neuroaxonal dystrophy and Dystonia-parkinsonism. While all three disorders give rise to similar defects in movement and cognition, some defects are unique to a specific disorder...
February 13, 2018: Scientific Reports
Shi-Lung Lin, Shin-Ju E Chang, Shao-Yao Ying
Transgenic animal models are valuable tools for testing gene functions and drug mechanisms in vivo. They are also the best similitude for a human body for etiological and pathological research of diseases. All pharmaceutically developed medicines must be proven to be safe and effective in animals before approval by the Food and Drug Administration (FDA) to be used in clinical trials. To this end, the transgenic animal models of diseases serve as the front line of drug evaluation. However, there is currently no transgenic animal model for microRNA (miRNA)-related research...
2018: Methods in Molecular Biology
Jana Schmidt, Thorsten Schmidt
Animal models are an important tool to study the pathophysiology of Machado-Joseph Disease (MJD). So far, animal models using simple organisms (like the round worm Caenorhabditis elegans or the fruit fly drosophila) but also mammalian models (mouse and even a non-human primate model) have been generated to study MJD. While simple organisms made an important contribution to the identification of pathophysiological mechanisms in MJD and were further used for modifier and screening purposes, mammalian models recapitulate major disease features of MJD in humans and are therefore a highly valuable tool for e...
2018: Advances in Experimental Medicine and Biology
Fabio Morgante, Wen Huang, Christian Maltecca, Trudy F C Mackay
Predicting complex phenotypes from genomic data is a fundamental aim of animal and plant breeding, where we wish to predict genetic merits of selection candidates; and of human genetics, where we wish to predict disease risk. While genomic prediction models work well with populations of related individuals and high linkage disequilibrium (LD) (e.g., livestock), comparable models perform poorly for populations of unrelated individuals and low LD (e.g., humans). We hypothesized that low prediction accuracies in the latter situation may occur when the genetics architecture of the trait departs from the infinitesimal and additive architecture assumed by most prediction models...
February 10, 2018: Heredity
Helio Roque, Saroj Saurya, Metta B Pratt, Errin Johnson, Jordan W Raff
Pericentrin is a conserved centrosomal protein whose dysfunction has been linked to several human diseases. It has been implicated in many aspects of centrosome and cilia function, but its precise role is unclear. Here, we examine Drosophila Pericentrin-like-protein (PLP) function in vivo in tissues that form both centrosomes and cilia. Plp mutant centrioles exhibit four major defects: (1) They are short and have subtle structural abnormalities; (2) They disengage prematurely, and so overduplicate; (3) They organise fewer cytoplasmic MTs during interphase; (4) When forming cilia, they fail to establish and/or maintain a proper connection to the plasma membrane-although, surprisingly, they can still form an axoneme-like structure that can recruit transition zone (TZ) proteins...
February 9, 2018: PLoS Genetics
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