Deciphering mechanisms of action of ACE inhibitors in neurodegeneration using models of Alzheimer's disease.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder for which there is no cure. Recently, several studies have reported a significant reduction in the incidence and progression of dementia among some patients receiving antihypertensive medications such as angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs). Why these drugs are beneficial in some AD patients and not others is unclear although it has been shown to be independent of their role in regulating blood pressure.

Glycoside hydrolase processing of the Pel polysaccharide alters biofilm biomechanics and Pseudomonas aeruginosa virulence.

Pel exopolysaccharide biosynthetic loci are phylogenetically widespread biofilm matrix determinants in bacteria. In Pseudomonas aeruginosa, Pel is crucial for cell-to-cell interactions and reducing susceptibility to antibiotic and mucolytic treatments. While genes encoding glycoside hydrolases have long been linked to biofilm exopolysaccharide biosynthesis, their physiological role in biofilm development is unclear.

Functional characterization of variants of unknown significance in a spinocerebellar ataxia patient using an unsupervised machine learning pipeline.

CAG-expanded ATXN7 has been previously defined in the pathogenesis of spinocerebellar ataxia type 7 (SCA7), a polyglutamine expansion autosomal dominant cerebellar ataxia. Pathology in SCA7 occurs as a result of a CAG triplet repeat expansion in excess of 37 in the first exon of ATXN7, which encodes ataxin-7. SCA7 presents clinically with spinocerebellar ataxia and cone-rod dystrophy.

Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers Rescue Memory Defects in -Expressing Alzheimer's Disease-Related Transgenes Independently of the Canonical Renin Angiotensin System.

Alzheimer's disease (AD) is a degenerative disorder that causes progressive memory and cognitive decline. Recently, studies have reported that inhibitors of the mammalian renin angiotensin system (RAS) result in a significant reduction in the incidence and progression of AD by unknown mechanisms. Here, we used a genetic and pharmacological approach to evaluate the beneficial effects of angiotensin converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) in expressing AD-related transgenes.

Chemical entrapment and killing of insects by bacteria.

Actinobacteria produce antibacterial and antifungal specialized metabolites. Many insects harbour actinobacteria on their bodies or in their nests and use these metabolites for protection. However, some actinobacteria produce metabolites that are toxic to insects and the evolutionary relevance of this toxicity is unknown.

Regulation of SH3PX1 by dNedd4-long at the neuromuscular junction.

Nedd4 (dNedd4) is a HECT E3 ubiquitin ligase present in two major isoforms: short (dNedd4S) and long (dNedd4Lo), with the latter containing two unique regions (N terminus and Middle). Although dNedd4S promotes neuromuscular synaptogenesis (NMS), dNedd4Lo inhibits it and impairs larval locomotion. To explain how dNedd4Lo inhibits NMS, MS analysis was performed to find its binding partners and identified SH3PX1, which binds dNedd4Lo unique Middle region.

An in vivo screen for neuronal genes involved in obesity identifies Diacylglycerol kinase as a regulator of insulin secretion.

Objective: Obesity is a complex disorder involving many genetic and environmental factors that are required to maintain energy homeostasis. While studies in human populations have led to significant progress in the generation of an obesity gene map and broadened our understanding of the genetic basis of common obesity, there is still a large portion of heritability and etiology that remains unknown. Here, we have used the genetically tractable fruit fly, Drosophila melanogaster, to identify genes/pathways that function in the nervous system to regulate energy balance.

Mutations in the Drosophila homolog of human PLA2G6 give rise to age-dependent loss of psychomotor activity and neurodegeneration.

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.

Drosophila mutants lacking octopamine exhibit impairment in aversive olfactory associative learning.

Octopamine is a biogenic amine in invertebrates that is considered a functional homolog of vertebrate norepinephrine, acting as a neurotransmitter, neuromodulator and neurohormone. Octopamine regulates many physiological processes such as metabolism, reproduction and different types of behaviour including learning and memory. Previous studies in insects led to the notion that acquisition of an olfactory memory depends on the octopaminergic system during appetitive (reward-based) learning, but not in the case of aversive (punishment-based) learning.

Diverse structures, functions and uses of FK506 binding proteins.

FK506 (Tacrolimus), isolated from Streptomyces tsukubaenis is a powerful immunosuppressant shown to inhibit T cell activation. FK506 mediated immunosuppression requires the formation of a complex between FK506, a FK506 binding protein (FKBP) and calcineurin. Numerous FKBPs have been identified in a wide range of species, from single celled organisms to humans.

The NHR domains of Neuralized and related proteins: Beyond Notch signalling.

Neuralized Homology Repeats (NHRs) were first identified in Neuralized, an E3-ubiquitin ligase that plays a key role in the Notch signalling pathway. Since their original discovery, NHR domains have been shown to regulate protein-protein interactions in a broad range of developmental processes and in a wide variety of species from flies to humans. The NHR family of proteins can be categorized into three groups: (1) those that contain a RING finger, (2) those that contain a SOCS box and, (3) those that only have NHR domains.

Psychomotor Behavior: A Practical Approach in Drosophila.

Psychomotor behaviors are governed by fine relationships between physical activity and cognitive functions. Disturbances in psychomotor development and performance are a hallmark of many mental illnesses and often appear as observable and measurable behaviors. Here, we describe a new method called an "equilibrist test," which can be used to quantify psychomotor learning and performance in Drosophila.

Drosophila Nedd4-long reduces Amphiphysin levels in muscles and leads to impaired T-tubule formation.

Drosophila Nedd4 (dNedd4) is a HECT ubiquitin ligase with two main splice isoforms: dNedd4-short (dNedd4S) and -long (dNedd4Lo). DNedd4Lo has a unique N-terminus containing a Pro-rich region. We previously showed that whereas dNedd4S promotes neuromuscular synaptogenesis, dNedd4Lo inhibits it and impairs larval locomotion.

Distinct Regulation of Transmitter Release at the Drosophila NMJ by Different Isoforms of nemy.

Synaptic transmission is highly plastic and subject to regulation by a wide variety of neuromodulators and neuropeptides. In the present study, we have examined the role of isoforms of the cytochrome b561 homologue called no extended memory (nemy) in regulation of synaptic strength and plasticity at the neuromuscular junction (NMJ) of third instar larvae in Drosophila. Specifically, we generated two independent excisions of nemy that differentially affect the expression of nemy isoforms.

Modeling obesity and its associated disorders in Drosophila.

In recent years, obesity has been recognized as a major public health problem due to its increased prevalence in both children and adults and its association with numerous life-threatening complications including diabetes, heart disease, hypertension, and cancer. Obesity is a complex disorder that is the result of the interaction between predisposing genetic and environmental factors. However, the precise nature of these gene-gene and gene-environment interactions remains unclear.

The BAR domain of amphiphysin is required for cleavage furrow tip-tubule formation during cellularization in Drosophila embryos.

De novo formation of cells in the Drosophila embryo is achieved when each nucleus is surrounded by a furrow of plasma membrane. Remodeling of the plasma membrane during cleavage furrow ingression involves the exocytic and endocytic pathways, including endocytic tubules that form at cleavage furrow tips (CFT-tubules). The tubules are marked by amphiphysin but are otherwise poorly understood.

big bang gene modulates gut immune tolerance in Drosophila.

Chronic inflammation of the intestine is detrimental to mammals. Similarly, constant activation of the immune response in the gut by the endogenous flora is suspected to be harmful to Drosophila. Therefore, the innate immune response in the gut of Drosophila melanogaster is tightly balanced to simultaneously prevent infections by pathogenic microorganisms and tolerate the endogenous flora.

FKBP14 is an essential gene that regulates Presenilin protein levels and Notch signaling in Drosophila.

Presenilins were identified as causative factors in familial Alzheimer's disease and also play an essential role in Notch signaling during development. We previously identified FKBP14, a member of the family of FK506-binding proteins (FKBPs), as a modifier of Presenilin in Drosophila. FKBPs are highly conserved peptidyl-prolyl cis-trans isomerases that play integral roles in protein folding, assembly and trafficking.

Functional analysis of the NHR2 domain indicates that oligomerization of Neuralized regulates ubiquitination and endocytosis of Delta during Notch signaling.

The Notch pathway plays an integral role in development by regulating cell fate in a wide variety of multicellular organisms. A critical step in the activation of Notch signaling is the endocytosis of the Notch ligands Delta and Serrate. Ligand endocytosis is regulated by one of two E3 ubiquitin ligases, Neuralized (Neur) or Mind bomb.

Healthy aging - insights from Drosophila.

Human life expectancy has nearly doubled in the past century due, in part, to social and economic development, and a wide range of new medical technologies and treatments. As the number of elderly increase it becomes of vital importance to understand what factors contribute to healthy aging. Human longevity is a complex process that is affected by both environmental and genetic factors and interactions between them.

The metabolism of histamine in the Drosophila optic lobe involves an ommatidial pathway: β-alanine recycles through the retina.

Flies recycle the photoreceptor neurotransmitter histamine by conjugating it to β-alanine to form β-alanyl-histamine (carcinine). The conjugation is regulated by Ebony, while Tan hydrolyses carcinine, releasing histamine and β-alanine. In Drosophila, β-alanine synthesis occurs either from uracil or from the decarboxylation of aspartate but detailed roles for the enzymes responsible remain unclear.

A splice isoform of DNedd4, DNedd4-long, negatively regulates neuromuscular synaptogenesis and viability in Drosophila.

Background: Neuromuscular (NM) synaptogenesis is a tightly regulated process. We previously showed that in flies, Drosophila Nedd4 (dNedd4/dNedd4S) is required for proper NM synaptogenesis by promoting endocytosis of commissureless from the muscle surface, a pre-requisite step for muscle innervation. DNedd4 is an E3 ubiquitin ligase comprised of a C2-WW(x3)-Hect domain architecture, which includes several splice isoforms, the most prominent ones are dNedd4-short (dNedd4S) and dNedd4-long (dNedd4Lo).

Liquid facets-related (lqfR) is required for egg chamber morphogenesis during Drosophila oogenesis.

Clathrin interactor 1 [CLINT1] (also called enthoprotin/EpsinR) is an Epsin N-terminal homology (ENTH) domain-containing adaptor protein that functions in anterograde and retrograde clathrin-mediated trafficking between the trans-Golgi network and the endosome. Removal of both Saccharomyces cerevisiae homologs, Ent3p and Ent5p, result in yeast that are viable, but that display a cold-sensitive growth phenotype and mistrafficking of various vacuolar proteins. Similarly, either knock-down or overexpression of vertebrate CLINT1 in cell culture causes mistrafficking of proteins.

Neurexins and neuroligins: recent insights from invertebrates.

During brain development, each neuron must find and synapse with the correct pre- and postsynaptic partners. The complexity of these connections and the relatively large distances some neurons must send their axons to find the correct partners makes studying brain development one of the most challenging, and yet fascinating disciplines in biology. Furthermore, once the initial connections have been made, the neurons constantly remodel their dendritic and axonal arbours in response to changing demands.

AP-1 and clathrin are essential for secretory granule biogenesis in Drosophila.

Regulated secretion of hormones, digestive enzymes, and other biologically active molecules requires the formation of secretory granules. Clathrin and the clathrin adaptor protein complex 1 (AP-1) are necessary for maturation of exocrine, endocrine, and neuroendocrine secretory granules. However, the initial steps of secretory granule biogenesis are only minimally understood.