scholarly journals Opposing functions for retromer and Rab11 in extracellular vesicle cargo traffic at presynaptic terminals

2019 ◽  
Author(s):  
Rylie B. Walsh ◽  
Agata N. Becalska ◽  
Matthew J. Zunitch ◽  
Tania Lemos ◽  
Erica C. Dresselhaus ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Motor Neuron ◽  
Intercellular Communication ◽  
Neurological Disease ◽  
Extracellular Vesicle ◽  
Presynaptic Terminals ◽  
Recycling Endosome ◽  
Retromer Complex ◽  
Shed Light ◽  
Competing Pathways

ABSTRACTNeuronal 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 Amyloid Precursor Protein (APP) and Synaptotagmin-4 (Syt4) at Drosophila motor neuron presynaptic terminals, resulting in increased release of these cargoes in EVs. By systematically exploring known retromer-dependent trafficking mechanisms, we show that EV regulation is separable from several previously identified roles of neuronal retromer, and depends on the ESCPE-1 complex. Conversely, loss of the recycling endosome regulator rab11 leads to reduced EV cargo levels, and suppresses cargo accumulation in retromer mutants. Thus, EV traffic reflects a balance between Rab11-mediated loading and retromer-dependent removal from EV precursor compartments. Our data shed light on previous studies implicating Rab11 and retromer in competing pathways in Alzheimer’s Disease, and suggest that misregulated EV traffic may be an underlying defect.

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

2021 ◽  
Vol 220 (8) ◽  
Author(s):  
Rylie B. Walsh ◽  
Erica C. Dresselhaus ◽  
Agata N. Becalska ◽  
Matthew J. Zunitch ◽  
Cassandra R. Blanchette ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Intercellular Communication ◽  
Neurological Disease ◽  
Extracellular Vesicle ◽  
Membrane Recycling ◽  
Presynaptic Terminals ◽  
Vesicle Traffic ◽  
Retromer Complex ◽  
Shed Light ◽  
Competing Pathways

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. By systematically exploring known retromer-dependent trafficking mechanisms, we show that EV regulation is separable from several previously identified roles of neuronal retromer. Conversely, mutations in rab11 and rab4, regulators of endosome-plasma membrane recycling, cause reduced EV cargo levels, and rab11 suppresses cargo accumulation in retromer mutants. Thus, EV traffic reflects a balance between Rab4/Rab11 recycling and retromer-dependent removal from EV precursor compartments. Our data shed light on previous studies implicating Rab11 and retromer in competing pathways in Alzheimer’s disease, and suggest that misregulated EV traffic may be an underlying defect.

Radical Capture at Ni(II) Complexes: C-C, C-N, and C-O Bond Formation

2019 ◽  
Author(s):  
Abolghasem (Gus) Bakhoda ◽  
Stefan Wiese ◽  
Christine Greene ◽  
Bryan C. Figula ◽  
Jeffery A. Bertke ◽  
...  
Keyword(s):  
Functional Groups ◽  
Bond Formation ◽  
Dft Studies ◽  
Bond Forming ◽  
Aryl Amines ◽  
Shed Light ◽  
Competing Pathways

<p>The dinuclear b-diketiminato Ni<sup>II</sup><i>tert</i>-butoxide {[Me<sub>3</sub>NN]Ni}<sub>2</sub>(<i>μ</i>-O<i><sup>t</sup></i>Bu)<sub>2 </sub>(<b>2</b>), synthesized from [Me<sub>3</sub>NN]Ni(2,4-lutidine) (<b>1</b>) and di-<i>tert</i>-butylperoxide, is a versatile precursor for the synthesis of a series of Ni<sup>II</sup>complexes [Me<sub>3</sub>NN]Ni-FG to illustrate C-C, C-N, and C-O bond formation at Ni<sup>II </sup>via radicals. {[Me<sub>3</sub>NN]Ni}<sub>2</sub>(<i>μ</i>-O<i><sup>t</sup></i>Bu)<sub>2 </sub>reacts with nitromethane, alkyl and aryl amines, acetophenone, benzamide, ammonia and phenols to deliver corresponding mono- or dinuclear [Me<sub>3</sub>NN]Ni-FG species (FG = O<sub>2</sub>NCH<sub>2</sub>, R-NH, ArNH, PhC(O)NH, PhC(O)CH<sub>2</sub>, NH<sub>2</sub>and OAr). Many of these Ni<sup>II </sup>complexes are capable of capturing the benzylic radical PhCH(•)CH<sub>3 </sub>to deliver corresponding PhCH(FG)CH<sub>3 </sub>products featuring C-C, C-N or C-O bonds. DFT studies shed light on the mechanism of these transformations and suggest two competing pathways that depend on the nature of the functional groups. These radical capture reactions at [Ni<sup>II</sup>]-FG complexes outline key C-C, C-N, and C-O bond forming steps and suggest new families of nickel radical relay catalysts.</p>

scholarly journals Cerebrospinal fluid extracellular vesicle enrichment for protein biomarker discovery in neurological disease; multiple sclerosis

2017 ◽  
Vol 6 (1) ◽  
pp. 1369805 ◽  
Author(s):  
Joanne L. Welton ◽  
Samantha Loveless ◽  
Timothy Stone ◽  
Chris von Ruhland ◽  
Neil P. Robertson ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cerebrospinal Fluid ◽  
Neurological Disease ◽  
Biomarker Discovery ◽  
Extracellular Vesicle ◽  
Protein Biomarker

Colorimetric Metasurfaces Shed Light on Fibrous Biological Tissue

2021 ◽  
Author(s):  
Zaid Haddadin ◽  
Trinity Pike ◽  
Jebin J. Moses ◽  
Lisa V. Poulikakos
Keyword(s):  
Heart Disease ◽  
Biological Tissue ◽  
Neurological Disease ◽  
Polarized Light ◽  
Fibrous Media ◽  
Shed Light

Fiber-affecting diseases - encompassing fibrosis, heart disease, neurological disease and cancer - are directly linked to the density and reorganization of fibrous media in biological tissue. Polarized light has unique...

scholarly journals An miRNA fingerprint using neural-enriched extracellular vesicles from blood plasma: towards a biomarker for amyotrophic lateral sclerosis/motor neuron disease

Open Biology ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 200116 ◽  
Author(s):  
Sandra Anne Banack ◽  
Rachael Anne Dunlop ◽  
Paul Alan Cox
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Blood Plasma ◽  
Motor Neuron ◽  
Motor Neuron Disease ◽  
Extracellular Vesicles ◽  
Disease Diagnosis ◽  
Extracellular Vesicle ◽  
Improve Patient ◽  
Lateral Sclerosis

Biomarkers for amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) are currently not clinically available for disease diagnosis or analysis of disease progression. If identified, biomarkers could improve patient outcomes by enabling early intervention and assist in the determination of treatment efficacy. We hypothesized that neural-enriched extracellular vesicles could provide microRNA (miRNA) fingerprints with unequivocal signatures of neurodegeneration. Using blood plasma from ALS/MND patients and controls, we extracted neural-enriched extracellular vesicle fractions and conducted next-generation sequencing and qPCR of miRNA components of the transcriptome. We here report eight miRNA sequences which significantly distinguish ALS/MND patients from controls in a replicated experiment using a second cohort of patients and controls. miRNA sequences from patient blood samples using neural-enriched extracellular vesicles may yield unique insights into mechanisms of neurodegeneration and assist in early diagnosis of ALS/MND.

scholarly journals Regulation of Eag by Ca2+/calmodulin controls presynaptic excitability in Drosophila

2018 ◽  
Vol 119 (5) ◽  
pp. 1665-1680 ◽  
Author(s):  
Peter Bronk ◽  
Elena A. Kuklin ◽  
Srinivas Gorur-Shandilya ◽  
Chang Liu ◽  
Timothy D. Wiggin ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Neurotransmitter Release ◽  
Cell Function ◽  
Large Family ◽  
Projection Neuron ◽  
Memory Formation ◽  
Presynaptic Terminals ◽  
Voltage Gated ◽  
Larval Neuromuscular Junction

Drosophila ether-à-go-go ( eag) is the founding member of a large family of voltage-gated K+ channels, the KCNH family, which includes Kv10, 11, and 12. Concurrent binding of calcium/calmodulin (Ca2+/CaM) to NH2- and COOH-terminal sites inhibits mammalian EAG1 channels at submicromolar Ca2+ concentrations, likely by causing pore constriction. Although the Drosophila EAG channel was believed to be Ca2+-insensitive (Schönherr R, Löber K, Heinemann SH. EMBO J 19: 3263–3271, 2000.), both the NH2- and COOH-terminal sites are conserved. In this study we show that Drosophila EAG is inhibited by high Ca2+ concentrations that are only present at plasma membrane Ca2+ channel microdomains. To test the role of this regulation in vivo, we engineered mutations that block CaM-binding to the major COOH-terminal site of the endogenous eag locus, disrupting Ca2+-dependent inhibition. eag CaMBD mutants have reduced evoked release from larval motor neuron presynaptic terminals and show decreased Ca2+ influx in stimulated adult projection neuron presynaptic terminals, consistent with an increase in K+ conductance. These results are predicted by a conductance-based multicompartment model of the presynaptic terminal in which some fraction of EAG is localized to the Ca2+ channel microdomains that control neurotransmitter release. The reduction of release in the larval neuromuscular junction drives a compensatory increase in motor neuron somatic excitability. This misregulation of synaptic and somatic excitability has consequences for systems-level processes and leads to defects in associative memory formation in adults. NEW & NOTEWORTHY Regulation of excitability is critical to tuning the nervous system for complex behaviors. We demonstrate in this article that the EAG family of voltage-gated K+ channels exhibit conserved gating by Ca2+/CaM. Disruption of this inhibition in Drosophila results in decreased evoked neurotransmitter release due to truncated Ca2+ influx in presynaptic terminals. In adults, disrupted Ca2+ dynamics cripples memory formation. These data demonstrate that the biophysical details of channels have important implications for cell function and behavior.

Regulation and mechanisms of extracellular vesicle biogenesis and secretion

2018 ◽  
Vol 62 (2) ◽  
pp. 125-133 ◽  
Author(s):  
Crislyn D’Souza-Schorey ◽  
Jeffrey S. Schorey
Keyword(s):  
Tumor Microenvironment ◽  
Intercellular Communication ◽  
Membrane Vesicles ◽  
Cell Types ◽  
Extracellular Vesicle ◽  
Systemic Delivery ◽  
Heterogeneous Membrane ◽  
Vesicle Biogenesis ◽  
Infected Cells ◽  
Pathogenic Agents

EV (extracellular vesicle) biology is a rapidly expanding field. These heterogeneous membrane vesicles, which are shed from virtually all cell types, collectively represent a new dimension of intercellular communication in normal physiology and disease. They have been shown to deliver infectious and pathogenic agents to non-infected cells whereas in cancers they are thought to condition the tumor microenvironment. Their presence in body fluids and inherent capacity for systemic delivery point to their clinical promise. All of the above only intensifies the need to better understand the classification, mode of biogenesis, and contents of the different subtypes of EVs. This article focusses on vesicle subtypes labeled as exosomes and MVs (microvesicles) and discusses the biogenesis and release of these vesicles from cells.

scholarly journals Extracellular vesicle mediated intercellular communication at the porcine maternal-fetal interface: A new paradigm for conceptus-endometrial cross-talk

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Mallikarjun Bidarimath ◽  
Kasra Khalaj ◽  
Rami T. Kridli ◽  
Frederick W. K. Kan ◽  
Madhuri Koti ◽  
...  
Keyword(s):  
Cross Talk ◽  
Intercellular Communication ◽  
Extracellular Vesicle ◽  
New Paradigm ◽  
Maternal Fetal Interface

Palliative care in non-malignant neurological disease

2010 ◽  
Author(s):  
Max Watson ◽  
Caroline Lucas ◽  
Andrew Hoy ◽  
Jo Wells
Keyword(s):  
Multiple Sclerosis ◽  
Palliative Care ◽  
Multiple System Atrophy ◽  
Motor Neuron ◽  
Progressive Supranuclear Palsy ◽  
Motor Neuron Disease ◽  
Symptom Management ◽  
Neurological Disease ◽  
Neurological Complications ◽  
Jakob Disease

This chapter focuses on the symptom management of multiple sclerosis, Parkinson’s disease, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), motor neuron disease, neurological complications of AIDS, Creutzfeldt-Jakob disease (CJD), and useful contacts.

scholarly journals miR-26a regulates extracellular vesicle secretion from prostate cancer cells via targeting SHC4, PFDN4, and CHORDC1

2020 ◽  
Vol 6 (18) ◽  
pp. eaay3051 ◽  
Author(s):  
Fumihiko Urabe ◽  
Nobuyoshi Kosaka ◽  
Yurika Sawa ◽  
Yusuke Yamamoto ◽  
Kagenori Ito ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
High Throughput ◽  
Intercellular Communication ◽  
Extracellular Vesicle ◽  
Prostate Cancer Cells ◽  
Biological Phenomena ◽  
Vesicle Secretion

Extracellular vesicles (EVs) are involved in intercellular communication during cancer progression; thus, elucidating the mechanism of EV secretion in cancer cells will contribute to the development of an EV-targeted cancer treatment. However, the biogenesis of EVs in cancer cells is not fully understood. MicroRNAs (miRNAs) regulate a variety of biological phenomena; thus, miRNAs could regulate EV secretion. Here, we performed high-throughput miRNA-based screening to identify the regulators of EV secretion using an ExoScreen assay. By using this method, we identified miR-26a involved in EV secretion from prostate cancer (PCa) cells. In addition, we found that SHC4, PFDN4, and CHORDC1 genes regulate EV secretion in PCa cells. Furthermore, the progression of the PCa cells suppressing these genes was inhibited in an in vivo study. Together, our findings suggest that miR-26a regulates EV secretion via targeting SHC4, PFDN4, and CHORDC1 in PCa cells, resulting in the suppression of PCa progression.

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