ESCRT disruption provides evidence against transsynaptic signaling functions for extracellular vesicles.

Extracellular vesicles (EVs) are released by many cell types including neurons, carrying cargoes involved in signaling and disease. It is unclear whether EVs promote intercellular signaling or serve primarily to dispose of unwanted materials. We show that loss of multivesicular endosome-generating ESCRT (endosomal sorting complex required for transport) machinery disrupts release of EV cargoes from motor neurons.

The enemy of my enemy: PTEN and PLCXD collude to fight endosomal PtdIns(4,5)P.

Loss of the phosphoinositide 5-phosphatase OCRL causes accumulation of PtdIns(4,5)P on membranes and, ultimately, Lowe syndrome. In this issue, Mondin et al. (2019.

Active Probes for Imaging Membrane Dynamics of Live Cells with High Spatial and Temporal Resolution over Extended Time Scales and Areas.

Despite the advancement of molecular imaging techniques, there is an unmet need for probes for direct imaging of membrane dynamics of live cells. Here we report a novel type of active (or enzyme responsive) probes to directly image membrane dynamics of live cells with high spatial and temporal resolution over extended time scales and areas. Because lipid rafts enrich cholesterols and GPI-anchored enzymes (e.

Cellular Uptake of A Taurine-Modified, Ester Bond-Decorated D-Peptide Derivative via Dynamin-Based Endocytosis and Macropinocytosis.

Most of the peptides used for promoting cellular uptake bear positive charges. In our previous study, we reported an example of taurine (bearing negative charges in physiological conditions) promoting cellular uptake of D-peptides. Taurine, conjugated to a small D-peptide via an ester bond, promotes the cellular uptake of this D-peptide.

The WAVE Regulatory Complex and Branched F-Actin Counterbalance Contractile Force to Control Cell Shape and Packing in the Drosophila Eye.

Contractile forces eliminate cell contacts in many morphogenetic processes. However, mechanisms that balance contractile forces to promote subtler remodeling remain unknown. To address this gap, we investigated remodeling of Drosophila eye lattice cells (LCs), which preserve cell contacts as they narrow to form the edges of a multicellular hexagonal lattice.

dOCRL maintains immune cell quiescence by regulating endosomal traffic.

Lowe Syndrome is a developmental disorder characterized by eye, kidney, and neurological pathologies, and is caused by mutations in the phosphatidylinositol-5-phosphatase OCRL. OCRL plays diverse roles in endocytic and endolysosomal trafficking, cytokinesis, and ciliogenesis, but it is unclear which of these cellular functions underlie specific patient symptoms. Here, we show that mutation of Drosophila OCRL causes cell-autonomous activation of hemocytes, which are macrophage-like cells of the innate immune system.

Drosophila comes of age as a model system for understanding the function of cytoskeletal proteins in cells, tissues, and organisms.

For the last 100 years, Drosophila melanogaster has been a powerhouse genetic system for understanding mechanisms of inheritance, development, and behavior in animals. In recent years, advances in imaging and genetic tools have led to Drosophila becoming one of the most effective systems for unlocking the subcellular functions of proteins (and particularly cytoskeletal proteins) in complex developmental settings. In this review, written for non-Drosophila experts, we will discuss critical technical advances that have enabled these cell biological insights, highlighting three examples of cytoskeletal discoveries that have arisen as a result: (1) regulation of Arp2/3 complex in myoblast fusion, (2) cooperation of the actin filament nucleators Spire and Cappuccino in establishment of oocyte polarity, and (3) coordination of supracellular myosin cables.

Segmentation and tracking of adherens junctions in 3D for the analysis of epithelial tissue morphogenesis.

Epithelial morphogenesis generates the shape of tissues, organs and embryos and is fundamental for their proper function. It is a dynamic process that occurs at multiple spatial scales from macromolecular dynamics, to cell deformations, mitosis and apoptosis, to coordinated cell rearrangements that lead to global changes of tissue shape. Using time lapse imaging, it is possible to observe these events at a system level.

Essential roles for stat92E in expanding and patterning the proximodistal axis of the Drosophila wing imaginal disc.

The Drosophila wing imaginal disc is subdivided along the proximodistal axis into the distal pouch, the hinge, the surrounding pleura, and the notum. While the genetic pathways that specify the identity of each of these domains have been well studied, the mechanisms that coordinate the relative expansion of these domains are not well understood. Here we investigated the role of the stat92E signal transducer and activator of transcription in wing proximodistal development.

odd-skipped genes and lines organize the notum anterior-posterior axis using autonomous and non-autonomous mechanisms.

The growth and patterning of Drosophila wing and notum primordia depend on their subdivision into progressively smaller domains by secreted signals that emanate from localized sources termed organizers. While the mechanisms that organize the wing primordium have been studied extensively, those that organize the notum are incompletely understood. The genes odd-skipped (odd), drumstick (drm), sob, and bowl comprise the odd-skipped family of C(2)H(2) zinc finger genes, which has been implicated in notum growth and patterning.

Inhibitors of cytochrome c release with therapeutic potential for Huntington's disease.

Release of mitochondrial cytochrome c resulting in downstream activation of cell death pathways has been suggested to play a role in neurologic diseases featuring cell death. However, the specific biologic importance of cytochrome c release has not been demonstrated in Huntington's disease (HD). To evaluate the role of cytochrome c release, we screened a drug library to identify new inhibitors of cytochrome c release from mitochondria.

Combined riluzole and sodium phenylbutyrate therapy in transgenic amyotrophic lateral sclerosis mice.

Recent evidence suggests that transcriptional dysregulation may play a role in the pathogenesis of amyotrophic lateral sclerosis (ALS). The histone deacetylase inhibitor, sodium phenylbutyrate (NaPB), is neuroprotective and corrects aberrant gene transcription in ALS mice and has recently been shown to be safe and tolerable in ALS patients while improving hypoacetylation. Since many patients are already on riluzole, it is important to ensure that any proposed therapy does not result in negative synergy with riluzole.

Therapeutic attenuation of mitochondrial dysfunction and oxidative stress in neurotoxin models of Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder for which there is no current therapy preventing cumulative neuronal loss. There is substantial evidence that mitochondrial dysfunction, oxidative stress, and associated caspase activity underlie the neurodegeneration observed. One potential drug therapy is the potent free radical scavenger and antioxidant cystamine, which has demonstrated significant clinical potential in models of neurodegenerative disorders and human neurological disease.

Modulation of nucleosome dynamics in Huntington's disease.

Transcriptional dysregulation and aberrant chromatin remodeling are central features in the pathology of Huntington's disease (HD). In order to more fully characterize these pathogenic events, an assessment of histone profiles and associated gene changes were performed in transgenic N171-82Q (82Q) and R6/2 HD mice. Analyses revealed significant chromatin modification, resulting in reduced histone acetylation with concomitant increased histone methylation, consistent with findings observed in HD patients.

Conformation-sensitive antibodies against alzheimer amyloid-beta by immunization with a thioredoxin-constrained B-cell epitope peptide.

Immunotherapy against the amyloid-beta (Abeta) peptide is a valuable potential treatment for Alzheimer disease (AD). An ideal antigen should be soluble and nontoxic, avoid the C-terminally located T-cell epitope of Abeta, and yet be capable of eliciting antibodies that recognize Abeta fibrils and neurotoxic Abeta oligomers but not the physiological monomeric species of Abeta. We have described here the construction and immunological characterization of a recombinant antigen with these features obtained by tandem multimerization of the immunodominant B-cell epitope peptide Abeta1-15 (Abeta15) within the active site loop of bacterial thioredoxin (Trx).

Dose ranging and efficacy study of high-dose coenzyme Q10 formulations in Huntington's disease mice.

There is substantial evidence that a bioenergetic defect may play a role in the pathogenesis of Huntington's Disease (HD). A potential therapy for remediating defective energy metabolism is the mitochondrial cofactor, coenzyme Q10 (CoQ10). We have reported that CoQ10 is neuroprotective in the R6/2 transgenic mouse model of HD.

Combination therapy using minocycline and coenzyme Q10 in R6/2 transgenic Huntington's disease mice.

Huntington's disease (HD) is a fatal neurodegenerative disorder of genetic origin with no known therapeutic intervention that can slow or halt disease progression. Transgenic murine models of HD have significantly improved the ability to assess potential therapeutic strategies. The R6/2 murine model of HD, which recapitulates many aspects of human HD, has been used extensively in pre-clinical HD therapeutic treatment trials.

Chronology of behavioral symptoms and neuropathological sequela in R6/2 Huntington's disease transgenic mice.

Genetic murine models play an important role in the study of human neurological disorders by providing accurate and experimentally accessible systems to study pathogenesis and to test potential therapeutic treatments. One of the most widely employed models of Huntington's disease (HD) is the R6/2 transgenic mouse. To characterize this model further, we have performed behavioral and neuropathological analyses that provide a foundation for the use of R6/2 mice in preclinical therapeutic trials.