NMNAT2:HSP90 Complex Mediates Proteostasis in Proteinopathies.
PLoS Biology 14(6):e1002472 (2016)
Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) is neuroprotective in numerous preclinical models of neurodegeneration. Here, we show that brain nmnat2 mRNA levels correlate positively with global cognitive function and negatively with AD pathology. In AD brains, NMNAT2 mRNA and prot...
Ubr3, a Novel Modulator of Hh Signaling Affects the Degradation of Costal-2 and Kif7 through Poly-ubiquitination.
PLoS Genetics 12(5):e1006054 (2016)
Hedgehog (Hh) signaling regulates multiple aspects of metazoan development and tissue homeostasis, and is constitutively active in numerous cancers. We identified Ubr3, an E3 ubiquitin ligase, as a novel, positive regulator of Hh signaling in Drosophila and vertebrates. Hh signaling regulates th...
Missense variants in the middle domain of DNM1L in cases of infantile encephalopathy alter peroxisomes and mitochondria when assayed in Drosophila.
Human Molecular Genetics 25(9):1846 (2016)
Defects in organelle dynamics underlie a number of human degenerative disorders, and whole exome sequencing (WES) is a powerful tool for studying genetic changes that affect the cellular machinery. WES may uncover variants of unknown significance (VUS) that require functional validation. Previou...
Drosophila tools and assays for the study of human diseases.
Disease Models & Mechanisms 9(3):235 (2016)
Many of the internal organ systems of Drosophila melanogaster are functionally analogous to those in vertebrates, including humans. Although humans and flies differ greatly in terms of their gross morphological and cellular features, many of the molecular mechanisms that govern development and d...
WAC Regulates mTOR Activity by Acting as an Adaptor for the TTT and Pontin/Reptin Complexes.
Developmental Cell 36(2):139 (2016)
The ability to sense energy status is crucial in the regulation of metabolism via the mechanistic Target of Rapamycin Complex 1 (mTORC1). The assembly of the TTT-Pontin/Reptin complex is responsive to changes in energy status. Under energy-sufficient conditions, the TTT-Pontin/Reptin complex pro...
Uncoupling neuronal death and dysfunction in Drosophila models of neurodegenerative disease.
Acta neuropathologica communications 4(1):62 (2016)
Common neurodegenerative proteinopathies, such as Alzheimer's disease (AD) and Parkinson's disease (PD), are characterized by the misfolding and aggregation of toxic protein species, including the amyloid beta (Aß) peptide, microtubule-associated protein Tau (Tau), and alpha-synuclein (αSyn) pro...
The E3 ligase Ubr3 regulates Usher syndrome and MYH9 disorder proteins in the auditory organs of Drosophila and mammals.
eLife 5 (2016)
Myosins play essential roles in the development and function of auditory organs and multiple myosin genes are associated with hereditary forms of deafness. Using a forward genetic screen in Drosophila, we identified an E3 ligase, Ubr3, as an essential gene for auditory organ development. Ubr3 ne...
Loss of Frataxin induces iron toxicity, sphingolipid synthesis, and Pdk1/Mef2 activation, leading to neurodegeneration.
eLife 5 (2016)
Mutations in Frataxin (FXN) cause Friedreich's ataxia (FRDA), a recessive neurodegenerative disorder. Previous studies have proposed that loss of FXN causes mitochondrial dysfunction, which triggers elevated reactive oxygen species (ROS) and leads to the demise of neurons. Here we describe a ROS...
Ig Superfamily Ligand and Receptor Pairs Expressed in Synaptic Partners in Drosophila.
Cell 163(7):1756 (2015)
Information processing relies on precise patterns of synapses between neurons. The cellular recognition mechanisms regulating this specificity are poorly understood. In the medulla of the Drosophila visual system, different neurons form synaptic connections in different layers. Here, we sought t...
Control of Synaptic Connectivity by a Network of Drosophila IgSF Cell Surface Proteins.
Cell 163(7):1770 (2015)
We have defined a network of interacting Drosophila cell surface proteins in which a 21-member IgSF subfamily, the Dprs, binds to a nine-member subfamily, the DIPs. The structural basis of the Dpr-DIP interaction code appears to be dictated by shape complementarity within the Dpr-DIP binding int...
Morgan's legacy: fruit flies and the functional annotation of conserved genes.
Cell 163(1):12 (2015)
In 1915, "The Mechanism of Mendelian Heredity" was published by four prominent Drosophila geneticists. They discovered that genes form linkage groups on chromosomes inherited in a Mendelian fashion and laid the genetic foundation that promoted Drosophila as a model organism. Flies continue to of...
BIOSAFETY. Safeguarding gene drive experiments in the laboratory.
Science 349(6251):927 (2015)
The retromer complex in development and disease.
Development 142(14):2392 (2015)
The retromer complex is a multimeric protein complex involved in recycling proteins from endosomes to the trans-Golgi network or plasma membrane. It thus regulates the abundance and subcellular distribution of its cargo within cells. Studies using model organisms show that the retromer complex i...
Impaired Mitochondrial Energy Production Causes Light-Induced Photoreceptor Degeneration Independent of Oxidative Stress.
PLoS Biology 13(7):e1002197 (2015)
Two insults often underlie a variety of eye diseases including glaucoma, optic atrophy, and retinal degeneration--defects in mitochondrial function and aberrant Rhodopsin trafficking. Although mitochondrial defects are often associated with oxidative stress, they have not been linked to Rhodopsi...
Correction: the retromer complex is required for rhodopsin recycling and its loss leads to photoreceptor degeneration.
PLoS Biology 13(5):e1002170 (2015)
[This corrects the article DOI: 10.1371/journal.pbio.1001847.].
A voltage-gated calcium channel regulates lysosomal fusion with endosomes and autophagosomes and is required for neuronal homeostasis.
PLoS Biology 13(3):e1002103 (2015)
Autophagy helps deliver sequestered intracellular cargo to lysosomes for proteolytic degradation and thereby maintains cellular homeostasis by preventing accumulation of toxic substances in cells. In a forward mosaic screen in Drosophila designed to identify genes required for neuronal function ...
Huntingtin functions as a scaffold for selective macroautophagy.
Nature Cell Biology 17(3):262 (2015)
Selective macroautophagy is an important protective mechanism against diverse cellular stresses. In contrast to the well-characterized starvation-induced autophagy, the regulation of selective autophagy is largely unknown. Here, we demonstrate that Huntingtin, the Huntington disease gene product...
Fruit flies in biomedical research.
Genetics 199(3):639 (2015)
Many scientists complain that the current funding situation is dire. Indeed, there has been an overall decline in support in funding for research from the National Institutes of Health and the National Science Foundation. Within the Drosophila field, some of us question how long this funding cru...
Glial lipid droplets and ROS induced by mitochondrial defects promote neurodegeneration.
Cell 160(1-2):177 (2015)
Reactive oxygen species (ROS) and mitochondrial defects in neurons are implicated in neurodegenerative disease. Here, we find that a key consequence of ROS and neuronal mitochondrial dysfunction is the accumulation of lipid droplets (LD) in glia. In Drosophila, ROS triggers c-Jun-N-terminal Kina...
FlyVar: a database for genetic variation in Drosophila melanogaster.
Database 2015 (2015)
FlyVar is a publicly and freely available platform that addresses the increasing need of next generation sequencing data analysis in the Drosophila research community. It is composed of three parts. First, a database that contains 5.94 million DNA polymorphisms found in Drosophila melanogaster d...