FAST SOLVER FOR DIFFUSIVE TRANSPORT TIMES ON DYNAMIC INTRACELLULAR NETWORKS.

The transport of particles in cells is influenced by the properties of intracellular networks they traverse while searching for localized target regions or reaction partners. Moreover, given the rapid turnover in many intracellular structures, it is crucial to understand how temporal changes in the network structure affect diffusive transport. In this work, we use network theory to characterize complex intracellular biological environments across scales.

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.

Non-muscle myosin II regulates presynaptic actin assemblies and neuronal mechanobiology.

Neuromuscular junctions (NMJs) are evolutionarily ancient, specialized contacts between neurons and muscles. Axons and NMJs must endure mechanical strain through a lifetime of muscle contraction, making them vulnerable to aging and neurodegenerative conditions. However, cellular strategies for mitigating this mechanical stress remain unknown.

Tyrosyl-tRNA synthetase has a noncanonical function in actin bundling.

Dominant mutations in tyrosyl-tRNA synthetase (YARS1) and six other tRNA ligases cause Charcot-Marie-Tooth peripheral neuropathy (CMT). Loss of aminoacylation is not required for their pathogenicity, suggesting a gain-of-function disease mechanism. By an unbiased genetic screen in Drosophila, we link YARS1 dysfunction to actin cytoskeleton organization.

Local regulation of extracellular vesicle traffic by the synaptic endocytic machinery.

Neuronal extracellular vesicles (EVs) are locally released from presynaptic terminals, carrying cargoes critical for intercellular signaling and disease. EVs are derived from endosomes, but it is unknown how these cargoes are directed to the EV pathway rather than for conventional endolysosomal degradation. Here, we find that endocytic machinery plays an unexpected role in maintaining a release-competent pool of EV cargoes at synapses.

Recycle before taking out the trash: ATG-9 exo-endocytosis links neuronal activity to autophagosome biogenesis.

In this issue of Neuron, Yang et al. show that autophagy machinery is tightly coupled to neuronal activity via endocytic cycling of the transmembrane protein ATG-9 at presynaptic terminals.

Opposing functions for retromer and Rab11 in extracellular vesicle traffic at presynaptic terminals.

Neuronal extracellular vesicles (EVs) play important roles in intercellular communication and pathogenic protein propagation in neurological disease. However, it remains unclear how cargoes are selectively packaged into neuronal EVs. Here, we show that loss of the endosomal retromer complex leads to accumulation of EV cargoes including amyloid precursor protein (APP), synaptotagmin-4 (Syt4), and neuroglian (Nrg) at Drosophila motor neuron presynaptic terminals, resulting in increased release of these cargoes in EVs.

TDP-43 dysfunction restricts dendritic complexity by inhibiting CREB activation and altering gene expression.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two related neurodegenerative diseases that present with similar TDP-43 pathology in patient tissue. TDP-43 is an RNA-binding protein which forms aggregates in neurons of ALS and FTD patients as well as in a subset of patients diagnosed with other neurodegenerative diseases. Despite our understanding that TDP-43 is essential for many aspects of RNA metabolism, it remains obscure how TDP-43 dysfunction contributes to neurodegeneration.

Mechanisms for biogenesis and release of neuronal extracellular vesicles.

Neurons release membrane-bound extracellular vesicles (EVs) carrying proteins, nucleic acids, and other cargoes to mediate neuronal development, plasticity, inflammation, regeneration, and degeneration. Functional studies and therapeutic interventions into EV-dependent processes will require a deep understanding of how neuronal EVs are formed and released. However, unraveling EV biogenesis and trafficking mechanisms is challenging, since there are multiple pathways governing generation of different types of EVs, which overlap mechanistically with each other, as well as with intracellular endolysosomal trafficking pathways.

Retromer subunit, VPS29, regulates synaptic transmission and is required for endolysosomal function in the aging brain.

Retromer, including Vps35, Vps26, and Vps29, is a protein complex responsible for recycling proteins within the endolysosomal pathway. Although implicated in both Parkinson's and Alzheimer's disease, our understanding of retromer function in the adult brain remains limited, in part because and are essential for development. In , we find that is dispensable for embryogenesis but required for retromer function in aging adults, including for synaptic transmission, survival, and locomotion.

The Impact of Sustained Immunization Regimens on the Antibody Response to Oligomannose Glycans.

The high mannose patch (HMP) of the HIV envelope protein (Env) is the structure most frequently targeted by broadly neutralizing antibodies; therefore, many researchers have attempted to use mimics of this region as a vaccine immunogen. In our previous efforts, vaccinating rabbits with evolved HMP mimic glycopeptides containing Man resulted in an overall antibody response targeting the glycan core and linker rather than the full glycan or Manα1→2Man tips of Man glycans. A possible reason could be processing of our immunogen by host serum mannosidases.

Nanoparticles binding to lipid membranes: from vesicle-based gels to vesicle tubulation and destruction.

While cells offer numerous inspiring examples in which membrane morphology and function are controlled by interactions with viruses or proteins, we still lack design principles for controlling membrane morphology in synthetic systems. With experiments and simulations, we show that spherical nanoparticles binding to lipid-bilayer membrane vesicles results in a remarkably rich set of collective morphologies that are controllable via the particle binding energy. We separately study cationic and anionic particles, where the adhesion is tuned by addition of oppositely charged lipids to the vesicles.

Higher-order assembly of Sorting Nexin 16 controls tubulation and distribution of neuronal endosomes.

The activities of neuronal signaling receptors depend heavily on the maturation state of the endosomal compartments in which they reside. However, it remains unclear how the distribution of these compartments within the uniquely complex morphology of neurons is regulated and how this distribution itself affects signaling. Here, we identified mechanisms by which Sorting Nexin 16 (SNX16) controls neuronal endosomal maturation and distribution.

Enzymatic Assemblies Disrupt the Membrane and Target Endoplasmic Reticulum for Selective Cancer Cell Death.

The endoplasmic reticulum (ER) is responsible for the synthesis and folding of a large number of proteins, as well as intracellular calcium regulation, lipid synthesis, and lipid transfer to other organelles, and is emerging as a target for cancer therapy. However, strategies for selectively targeting the ER of cancer cells are limited. Here we show that enzymatically generated crescent-shaped supramolecular assemblies of short peptides disrupt cell membranes and target ER for selective cancer cell death.

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.

TDP-43 misexpression causes defects in dendritic growth.

Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) share overlapping genetic causes and disease symptoms, and are linked neuropathologically by the RNA binding protein TDP-43 (TAR DNA binding protein-43 kDa). TDP-43 regulates RNA metabolism, trafficking, and localization of thousands of target genes. However, the cellular and molecular mechanisms by which dysfunction of TDP-43 contributes to disease pathogenesis and progression remain unclear.

An in situ Dynamic Continuum of Supramolecular Phosphoglycopeptides Enables Formation of 3D Cell Spheroids.

Higher-order assemblies of proteins, with a structural and dynamic continuum, is an important concept in biology, but these insights have yet to be applied in designing biomaterials. Dynamic assemblies of supramolecular phosphoglycopeptides (sPGPs) transform a 2D cell sheet into 3D cell spheroids. A ligand-receptor interaction between a glycopeptide and a phosphopeptide produces sPGPs that form nanoparticles, which transform into nanofibrils upon partial enzymatic dephosphorylation.

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.