@article {737, title = {Lipid metabolic perturbation is an early-onset phenotype in adultmutants: amodel for lysosomal storage disorders. [Mass Spectrometry - Lipidomics]}, journal = {Mol Biol Cell}, volume = {28}, year = {2017}, month = {2017 Dec 15}, pages = {3728-3740}, abstract = {

Intracellular accumulation of lipids and swollen dysfunctional lysosomes are linked to several neurodegenerative diseases, including lysosomal storage disorders (LSD). Detailed characterization of lipid metabolic changes in relation to the onset and progression of neurodegeneration is currently missing. We systematically analyzed lipid perturbations inmutants, amodel of LSD-like neurodegeneration. Our results highlight an imbalance in brain ceramide and sphingosine in the early stages of neurodegeneration, preceding the accumulation of endomembranous structures, manifestation of altered behavior, and buildup of lipofuscin. Manipulating levels ofand altering these lipids inmutants allowed us to conclude that ceramide homeostasis is the driving force in disease progression and is integral tofunction in the adult nervous system. We identified 29 novel physical interaction partners of Spin and focused on the lipid carrier protein, Lipophorin (Lpp). A subset of Lpp and Spin colocalize in the brain and within organs specialized for lipid metabolism (fat bodies and oenocytes). Reduced Lpp protein was observed inmutant tissues. Finally, increased levels of lipid metabolites produced by oenocytes inmutants allude to a functional interaction between Spin and Lpp, underscoring the systemic nature of lipid perturbation in LSD.

}, keywords = {Animals, Carrier Proteins, Disease Models, Animal, Drosophila, Drosophila Proteins, Lipid Metabolism, Lipids, Lipoproteins, Lysosomal Storage Diseases, Lysosomes, Membrane Proteins, Mutation, Nervous System, Neurodegenerative Diseases, Phenotype}, issn = {1939-4586}, doi = {10.1091/mbc.E16-09-0674}, author = {Hebbar, Sarita and Khandelwal, Avinash and Jayashree, R and Hindle, Samantha J and Chiang, Yin Ning and Yew, Joanne Y and Sweeney, Sean T and Schwudke, Dominik} } @article {476, title = {The E3 ligase ube3a is required for learning in Drosophila melanogaster. [Drosophila facility]}, journal = {Biochem Biophys Res Commun}, volume = {462}, year = {2015}, month = {2015 Jun 19}, pages = {71-7}, abstract = {

Angelman syndrome and autism are neurodevelopmental disorders linked to mutations and duplications of an E3 ligase called ube3a respectively. Since cognitive deficits and learning disabilities are hallmark symptoms of both these disorders, we investigated a role for dube3a in the learning ability of flies using the aversive phototaxis suppression assay. We show that down and up-regulation of dube3a are both detrimental to learning in larvae and adults. Using conditional gene expression we found that dube3a is required for normal brain development and during adulthood. Furthermore, we suggest that dube3a could be interacting with other learning and memory genes such as derailed. Along with firmly establishing dube3a as a gene that is required for learning, our work also opens avenues for further understanding the role played by this gene in brain development and behavior.

}, keywords = {Animals, Animals, Genetically Modified, Brain, Drosophila melanogaster, Drosophila Proteins, Gene Expression Regulation, Developmental, Immunoblotting, Larva, Learning, Memory, Motor Activity, Mushroom Bodies, Mutation, Reverse Transcriptase Polymerase Chain Reaction, Time Factors, Ubiquitin-Protein Ligases}, issn = {1090-2104}, doi = {10.1016/j.bbrc.2015.04.110}, author = {Chakraborty, Moumita and Paul, Blesson K and Nayak, Tanmoyita and Das, Aniruddha and Jana, Nihar R and Bhutani, Supriya} } @article {478, title = {Functional implementation of Drosophila itpr mutants by rat Itpr1. [Drosophila facility]}, journal = {J Neurogenet}, volume = {26}, year = {2012}, month = {2012 Sep}, pages = {328-37}, abstract = {

The Drosophila inositol 1,4,5-trisphosphate receptor (IP(3)R) and mammalian type-1 IP(3)Rs have 57-60\% sequence similarity and share major domain homology with each other. Mutants in the single Drosophila IP(3)R gene, itpr, and Itpr1 knockout mice both exhibit lethality and defects in motor coordination. Here the authors show that the rat type-1 IP(3)R, which is the major neuronal isoform, when expressed in the pan-neuronal domain in Drosophila, functionally complements Drosophila IP(3)R function at cellular and systemic levels. It rescues the established neuronal phenotypes of itpr mutants in Drosophila, including wing posture, flight, electrophysiological correlates of flight maintenance, and intracellular calcium dynamics. This is the first in vivo demonstration of functional homology between a mammalian and fly IP(3)R. This study also paves the way for cellular and molecular analyses of the spinocerebellar ataxias in Drosophila, since SCA15/16 is known to be caused by heterozygosity of human ITPR1.

}, keywords = {Animals, Animals, Genetically Modified, Calcium, Cells, Cultured, Cytosol, Drosophila, Drosophila Proteins, Flight, Animal, Gene Expression Regulation, Genetic Therapy, Inositol 1,4,5-Trisphosphate Receptors, Larva, Movement Disorders, Mutation, Neurons, Physical Stimulation, Rats, Transcription Factors, Wings, Animal}, issn = {1563-5260}, doi = {10.3109/01677063.2012.697501}, author = {Chakraborty, Sumita and Hasan, Gaiti} } @article {483, title = {Inositol 1,4,5-trisphosphate receptor and dSTIM function in Drosophila insulin-producing neurons regulates systemic intracellular calcium homeostasis and flight. [Drosophila facility]}, journal = {J Neurosci}, volume = {30}, year = {2010}, month = {2010 Jan 27}, pages = {1301-13}, abstract = {

Calcium (Ca(2+)) signaling is known to regulate the development, maintenance and modulation of activity in neuronal circuits that underlie organismal behavior. In Drosophila, intracellular Ca(2+) signaling by the inositol 1,4,5-trisphosphate receptor and the store-operated channel (dOrai) regulates the formation and function of neuronal circuits that control flight. Here, we show that restoring InsP(3)R activity in insulin-producing neurons of flightless InsP(3)R mutants (itpr) during pupal development can rescue systemic flight ability. Expression of the store operated Ca(2+) entry (SOCE) regulator dSTIM in insulin-producing neurons also suppresses compromised flight ability of InsP(3)R mutants suggesting that SOCE can compensate for impaired InsP(3)R function. Despite restricted expression of wild-type InsP(3)R and dSTIM in insulin-producing neurons, a global restoration of SOCE and store Ca(2+) is observed in primary neuronal cultures from the itpr mutant. These results suggest that restoring InsP(3)R-mediated Ca(2+) release and SOCE in a limited subset of neuromodulatory cells can influence systemic behaviors such as flight by regulating intracellular Ca(2+) homeostasis in a large population of neurons through a non-cell-autonomous mechanism.

}, keywords = {Animals, Calcium, Calcium Signaling, Cell Membrane, Cells, Cultured, Central Nervous System, Drosophila, Drosophila Proteins, Flight, Animal, Homeostasis, Inositol 1,4,5-Trisphosphate Receptors, Insulin, Intracellular Fluid, Membrane Proteins, Mutation, Neural Pathways, Neurons, Pupa, Stromal Interaction Molecule 1}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.3668-09.2010}, author = {Agrawal, Neha and Venkiteswaran, Gayatri and Sadaf, Sufia and Padmanabhan, Nisha and Banerjee, Santanu and Hasan, Gaiti} }