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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 505 records · Page 28
All sourcesNASA NTRSDOE OSTI
DOE OSTI2018

Intrauterine exosomes are required for bovine conceptus implantation

Highlights: • Exosomes derived from the conceptuses acted on the endometrial epithelium. • Global protein analysis identified 596 exosomal proteins during peri-implantation. • Exosomes at pre-implantation up-regulated apoptosis-related genes in uterine cells. • Exosomes at post-implantation up-regulated adhesion molecule in uterine cells. Exosomes, extracellular vesicles, are present in uterine flushing fluids (UFs), which are involved in conceptus-endometrial interactions during peri-implantation periods. Despite several studies on intrauterine exosomes conducted, the roles conceptus and endometrial exosomes play during peri-implantation periods have not been well characterized. To investigate the effect of bovine intrauterine exosomes on conceptus implantation, exosomes isolated from bovine UFs during peri-implantation periods were subjected to global protein analysis. The analysis detected 596 exosomal proteins, including ruminants' pregnancy recognition factor IFNT, and 172 differentially expressed proteins with more than 1.5-fold changes in UFs on days 17, 20 and 22 pregnancy (day of conceptus implantation is initiated on days 19–19.5). Treatment of primary bovine endometrial epithelial cells with exosomes from day 17 UFs up-regulated the expression of apoptosis-related genes, and treatment with exosomes from day 20 and 22 UFs up-regulated the expression of adhesion molecule. Based on these findings, intrauterine exosomes should be considered as an essential constituent for successful implantation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Effects of dietary glucose and sodium chloride on intestinal glucose absorption of common carp (Cyprinus carpio L.)

Highlights: • Glucose absorption was primarily occurred in proximal and mid intestine in carp. • Food intake promoted SGLT1 and GLUT2 expressions, glucose transport in carp. • Dietary glucose promoted SGLT1 and GLUT2 expressions, glucose transport in carp. • Dietary NaCl enhanced SGLT1 and GLUT2 expressions, glucose transport in carp. • High-glucose diet increased while high-NaCl decreased intestinal villus height. The co-transport of sodium and glucose is the first step for intestinal glucose absorption. Dietary glucose and sodium chloride (NaCl) may facilitate this physiological process in common carp (Cyprinus carpio L.). To test this hypothesis, we first investigated the feeding rhythm of intestinal glucose absorption. Carps were fed to satiety once a day (09:00 a.m.) for 1 month. Intestinal samples were collected at 01:00, 05:00, 09:00, 13:00, 17:00 and 21:00. Result showed that food intake greatly enhanced sodium/glucose cotransporter 1 (SGLT1) and glucose transporter type 2 (GLUT2) expressions, and improved glucose absorption, with highest levels at 09:00 a.m.. Then we designed iso-nitrogenous and iso-energetic diets with graded levels of glucose (10%, 20%, 30%, 40% and 50%) and NaCl (0%, 1%, 3% and 5%), and submitted to feeding trial for 10 weeks. The expressions of SGLT1 and GLUT2, brush border membrane vesicles (BBMVs) glucose transport and intestinal villus height were determined after the feeding trial. Increasing levels of dietary glucose and NaCl up-regulated mRNA and protein levels of SGLT1 and GLUT2, enhanced BBMVs glucose transport in the proximal, mid and distal intestine. As for histological adaptive response, however, high-glucose diet prolonged while high-NaCl diet shrank intestinal villus height. Furthermore, we also found that higher mRNA levels of SGLT1 and GLUT2, higher glucose transport capacity of BBMVs, and higher intestinal villus were detected in the proximal and mid intestine, compared to the distal part. Taken together, our study indicated that intestinal glucose absorption in carp was primarily occurred in the proximal and mid intestine, and increasing levels of dietary glucose and NaCl enhanced intestinal glucose absorption in carp.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Suppression of tau propagation using an inhibitor that targets the DK-switch of nSMase2

Highlights: • Cambinol inhibits spread of AD synaptosome derived tau seeds, from donor to recipient cells. • Cambinol inhibits nSMase2 through targeting the DK-switch in its active site. • Cambinol inhibits EV-mediated tau propagation. • Cambinol has low brain permeability and inhibition of nSMase activity in vivo. Targeting of molecular pathways involved in the cell-to-cell propagation of pathological tau species is a novel approach for development of disease-modifying therapies that could block tau pathology and attenuate cognitive decline in patients with Alzheimer's disease and other tauopathies. We discovered cambinol through a screening effort and show that it is an inhibitor of cell-to-cell tau propagation. Our in vitro data demonstrate that cambinol inhibits neutral sphingomyelinase 2 (nSMase2) enzyme activity in dose response fashion, and suppresses extracellular vesicle (EV) production while reducing tau seed propagation. Our in vivo testing with cambinol shows that it can reduce the nSMase2 activity in the brain after oral administration. Our molecular docking and simulation analysis reveals that cambinol can target the DK-switch in the nSMase2 active site.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Exosomal proteome analysis of human plasma to monitor sepsis progression

Highlights: • As low as 300 μL human plasma is sufficient for exosome isolation using our one-step density gradient ultracentrifugation. • Protein profiling of septic plasma exosomes are closely related to immune responses. • SPTLC3 may play important roles in development of sepsis. Exosomes are cell-derived vesicles containing RNA, lipid, and protein, which act in body immune response, intercellular signaling and some other important biological processes. Exosomes have been extensively studied in the past several years on their disease related mechanisms and potential roles to monitor disease progression as biomarkers. Compared with analyzing exosome RNA, comprehensive proteome profiling of exosomes in clinical samples (e.g. blood) are highly demanded but limited mainly due to lack of a reproducible method for efficient exosome extraction. In this study, we evaluated and optimized an exosome preparation approach using one-step ultracentrifugation through an Optiprep™ cushion. Exosomes prepared via this method and analyzed by mass spectrometry using Q-Exactive plus, has led to reproducible identification and quantification of 200 + proteins from human plasma samples of as little as 300 μL. Therefore, such a straightforward exosome extract method has enable us to deeply profile exosome proteomes from human blood at a scale of clinical studies. As a proof of principal, we practiced this approach in analyzing the exosome proteomic profiles of blood samples collected from a sepsis patient during six time points after diagnosis. Among the 238 proteins identified and quantified across the 6 samples, protein SPTLC3 involved in the sphingolipid metabolism, shows a negative correlation (p = 0.02, correlation coefficient = −0.984) with disease progression indicated by body temperature (BD) and C-reactive protein (CRP). Therefore, SPTLC3 could be an interesting target for future study on molecular mechanism of sepsis development, as well as potential classifier to monitor clinical progression of sepsis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

LL-37-induced human osteoblast cytotoxicity and permeability occurs independently of cellular LL-37 uptake through clathrin-mediated endocytosis

Highlights: • LL-37 reduces viability and increases permeability of human osteoblast-like cells. • Chlorpromazine, inhibitor of clathrin-mediated endocytosis, reduces LL-37 import. • LL-37-induced cytotoxicity is unaffected by clathrin-mediated endocytosis block. • Knockdown of clathrin heavy chain gene attenuates uptake of LL-37. • Knockdown of clathrin heavy chain gene has no impact on LL-37-induced cytotoxicity. The host defense peptide LL-37 is cytotoxic for bacteria but it has also been reported to reduce host cell viability through an intracellular mechanism. LL-37-evoked cytotoxicity may be involved in the loss of bone tissue in periodontitis which is an inflammatory disease characterized by high concentrations of LL-37 observed locally in the periodontal tissue at the inflammation process. Here, we showed that LL-37 reduced human osteoblast-like MG63 cell viability assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and increased plasma membrane permeability determined by measuring intracellular Ca{sup 2+} levels and lactate dehydrogenase (LDH) release. Treatment with chlorpromazine, a well-recognized inhibitor of clathrin-mediated endocytosis, reduced cellular uptake of synthesized LL-37 b y about 30% assessed by Western blotting and ELISA, while filipin, an inhibitor of caveolin-mediated endocytosis, had no effect. The chlorpromazine-induced attenuation of LL-37 uptake was not associated with modulation of LL-37-induced cytotoxicity and LL-37-evoked plasma membrane permeability. Clathrin heavy chain 2 is a major protein of the polyhedral coat of coated pits and vesicles encoded by clathrin heavy chain like 1 gene. Down-regulation of clathrin heavy chain like 1 gene activity by siRNA reduced uptake of LL-37 but did not affect LL-37-induced cytotoxicity and permeability. Thus, we show, using both a pharmacological approach and knockdown of clathrin heavy chain like 1 expression, that LL-37-induced MG63 cell cytotoxicity and permeability occurs independently of LL-37 uptake via clathrin-mediated endocytosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Tumor-dependent secretion of close homolog of L1 results in elevation of its circulating level in mouse model for human lung tumor

Highlights: • CHL1 was secreted with truncated and exosomal form from primary lung tumor cells. • A mouse model for human lung tumor showed elevated circulating levels of CHL1. • The circulating CHL1 was increased in tumor size-dependent manner. • It suggests CHL1 is a potential indicator for tumor progression in human lung tumor. Close homolog of L1 (CHL1) and its truncated form mainly play crucial roles in mouse brain development and neural functions. Herein, we newly identified that truncated form of CHL1 is produced and released from lung tumor tissue in a mouse model expressing human EML4-ALK fusion gene. Both western blot and direct ELISA analysis revealed that mouse CHL1 level in serum (including serum extracellular vesicles) was significantly elevated in EML4-ALK transgenic mice. The correlation between the tumor size and the amount of CHL1 secretion could be examined in this study, and showed a significant positive correlation in a tumor size-dependent manner. Considering these results, the measurement of circulating CHL1 level may contribute to assess a tumor progression in human lung tumor patients.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Membrane proteins significantly restrict exosome mobility

Exosomes are membrane nanovesicles implicated in cell-to-cell signaling in which they transfer their molecular cargo from the parent to the recipient cells. This role essentially depends on the exosomes' small size, which is the prerequisite for their rapid migration through the crowded extracellular matrix and into and out of circulation. Here we report much lower exosome mobility than expected from the size of their vesicles, implicate membrane proteins in a substantially impeded rate of migration, and suggest an approach to quantifying the impact. The broadly distributed excess hydrodynamic resistance provided by surface proteins produces a highly heterogeneous and microenvironment-dependent hindrance to exosome mobility. The implications of the findings on exosome-mediated signaling are discussed.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Tissue factor mediates microvesicles shedding from MDA-MB-231 breast cancer cells

Highlights: • TF knockout in MDA-MB-231 cells reduced TF/FVIIa signaling and coagulation activity. • Silencing of TF in MDA-MB-231 cells decreased the release of MVs. • RhoA expression is decreased in TF-silenced MDA-MB-231 cells. • The ROCK inhibitor, fasudil, decreases MVs shedding by MDA-MB-231 cells. Extracellular vesicles, such as microvesicles (MVs), were identified as important players in tumor progression and acquisition of an aggressive phenotype. Tissue factor (TF) is a transmembrane protein that initiates the blood coagulation cascade. In tumor cells, TF has been associated with aggressiveness and cancer progression. Previous studies demonstrate that TF is incorporated into MVs secreted by tumor cells; however, it is unknown whether TF is actively involved in the release of MVs. Here, we investigated the influence of TF expression on the release of MVs. TF silencing was achieved through CRISPR/Cas9 approaches in the human breast cancer cell line, MDA-MB-231. TF knockout in MDA-MB-231 cells efficiently reduced TF-dependent signaling and procoagulant activity. Remarkably, silencing of TF caused a significant decrease in the number of MVs released by MDA-MB-231 cells. We also observed an increase in actin-positive membrane projections in TF knockout cells and a reduction in RhoA expression when compared to TF-expressing cells. Treatment of MDA-MB-231 cells with the RhoA-ROCK signaling pathway inhibitor, fasudil, significantly reduced the release of MVs. Taken together, our results suggest a novel and relevant role for TF in tumor biology by playing an active role in the MVs secretion.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Hypoxic glioblastoma release exosomal VEGF-A induce the permeability of blood-brain barrier

Exosomes are nano-vesicles released by tumor cells to modulate extracellular environment. Accumulating evidence revealed that glioblastoma derived exosomes contain multiple pro-angiogenic factors to induce the proliferation of endothelial cells. Here, we investigated the role of GBM-derived exosomes in inducing the permeability of the blood-brain barrier. We found that VEGF-A was over-expressed in hypoxic GBM-derived exosomes, which enhance the permeability of a BBB in vitro model by interrupting the expression of claudin-5 and occludin. In vivo permeability assay showed hypoxic GBM-derived exosomes remained functional in the blood circulation and induced the permeability of BBB.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Plasma exosomes regulate systemic blood pressure in rats

Highlights: • Roles of exosomes on regulation of essential hypertension remain to be determined. • Plasma exosomes modulated systemic blood pressure in normotensive and hypertensive rats. • Plasma exosomes modestly changed structure and function of cardiovascular tissues. • Present findings indicate exosomes are potential target for treatment of essential hypertension. Exosomes, the smallest extracellular vesicle, contain various molecules and mediate cell-cell communication. A number of studies demonstrate exosomes are involved in important physiological and pathological processes. Moreover, microRNA (miRNA) regulating hypertension development through the suppression of certain translation was recently reported. However, roles of exosomes containing various molecules including miRNA on development of essential hypertension have not been examined. We tested the hypothesis that plasma exosomes regulate systemic blood pressure in normotensive and spontaneously hypertensive rats (SHR). Normotensive Wistar Kyoto rats (WKY) and SHR (5-10-week-old) were intraperitoneally administrated with exosomes derived from plasma in WKY or SHR weekly for 6 weeks. Exosomes were isolated by an ultracentrifuge method. SHR-derived exosomes significantly increased systolic blood pressure in WKY, while WKY-derived exosomes decreased it in SHR. In WKY, SHR-derived exosomes induced modest structural changes of thoracic aorta, such as wall thickening and decreased abundance of collagen, which were similar to the changes observed in SHR. On the contrary, WKY-derived exosomes tended to reverse the changes in SHR. WKY-derived exosomes significantly suppressed the increased prostaglandin F{sub 2α}-induced contraction of mesenteric arterial smooth muscle in SHR. In addition, wet weight and perivascular fibrosis of left ventricles in WKY were significantly increased by SHR-derived exosomes, while the fibrosis but not ventricular weight was significantly decreased by WKY-derived exosomes in SHR. We for the first time demonstrated that plasma exosomes can modulate systemic blood pressure as well as structure and function of cardiovascular tissues in both normotensive and hypertensive rats.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Crucial role of Reg I from acinar-like cell cluster touching with islets (ATLANTIS) on mitogenesis of beta cells in EMC virus-induced diabetic mice

Recently, we reported the presence of distinct cell clusters named acinar-like cell clusters touching Langerhans islets with thin interstitial surrounding (ATLANTIS) in human pancreas. A morphological study in humans demonstrated that ATLANTIS and islet cell clusters are found together in the microenvironment enclosed by a common basement membrane, and ATLANTIS releases vesicles containing Regenerating gene protein (REG Iα) to islet cell clusters. We examined 1) the presence or absence of ATLANTIS in homozygous Reg I (mouse homologue of human REG Iα) deficient (Reg I{sup −/-}) and wild-type mice, and 2) the possible role of ATLANTIS in the regeneration of beta cell clusters after encephalomyocarditis (EMC) virus (D-variant) infection in Reg I{sup −/-} and wild-type mice. ATLANTIS was found in both wild-type and Reg I{sup −/-} mice. In both groups, mean blood glucose increased transiently to greater than 14.0 mmol/L at 5 days after EMC virus infection and recovered to baseline at 12 days. At 12 days after EMC virus infection, lower BrdU labeling indices were observed in islet beta cells of Reg I{sup −/-} mice compared to wild-type mice. Beta cell volume 12 days after EMC virus infection in Reg I{sup −/-} mice did not differ from that of wild-type mice. These results suggest that Reg I, which is released from ATLANTIS to islet beta cell clusters, has a crucial role in beta cell regeneration in EMC virus-induced diabetes. The presence of mechanism(s) other than that mediated by Reg I in beta cell restoration after destruction by EMC virus was also suggested.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

A revisit of the conformational dynamics of SNARE protein rYkt6

N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins are involved in the fusion of vesicles with their target membranes. R-SNARE protein Ykt6 is one of the most conserved SNARE in eukaryotes. The conformational state of Ykt6 is regulated by the lipidations at its C-terminal motif. Previous studies show that the binding of dodecylphosphocholine (DPC) can stabilize a closed conformation of rat Ykt6 (rYkt6) and mimic the farnesylated rYkt6. Despite this model, the detailed conformational dynamics of Ykt6 is still unclear. Here, we combined smFRET and MD simulation to demonstrate that the un-lipidated rYkt6 adopts five major conformational states. DPC binding shifts the conformational distribution toward the more closed states. At the same time, there remain considerable fractions of open and semi-open conformations in the presence of DPC. These newly revealed dynamic features of rYkt6 are consistent with its unique functional diversity in neuronal cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Pigment epithelium derived factor (PEDF) expression in the male tract of Wistar rats

Highlights: • PEDF expression is detected in epididymal tract of male rats. • PEDF expression was not detected in rat testes. • PEDF expression was decreased by using flutamide. • PEDF expression was recovered after flutamide cessation. Pigment epithelium derived factor (PEDF) expression has been described in many organs as showing neurotrophic, anti-angiogenic, anti-apoptotic, anti-inflammatory, anti-oxidant and pro-cell survival properties. However, references to its activity in the male reproductive system are scarce. We aimed to characterize the expression of PEDF in the male reproductive tract of Wistar rats by using RT-PCR, western blot and immunostaining and also evaluate the effect of flutamide in PEDF expression. We found that PEDF is expressed in the epididymis, prostate and seminal vesicles in Wistar rats, but notably not in the testes. Under the effect of flutamide PEDF expression decreased, recovering by suppressing the antiandrogen. The epididymis is an essential organ in sperm maturation-storages. The role of PEDF in this physiological process has not been fully elucidated yet, but considering that in other systems PEDF has anti-apoptotic, anti-oxidants and pro-cell survival properties, its expression along the epididymis could play a role in the protection of spermatozoa while they are stored.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Maturation and fertilization of echinoderm eggs: Role of actin cytoskeleton dynamics

Highlights: • Meiotic maturation of starfish oocytes involves the rearrangement of actin filaments and intracellular Ca{sup 2+} increases. • The actin cytoskeleton plays a role in optimizing the Ca{sup 2+} release mechanisms during oocyte maturation. • F-actin dynamics regulates Ca{sup 2+} signaling and cortical granules exocytosis at fertilization in starfish and sea urchin eggs. • Monospermic fertilization is heavily dependent upon the integrity of the actin cytoskeleton of the egg cortex. Starfish and sea urchin are excellent models to study the mechanisms that regulate oocyte maturation and egg activation. Hormonal stimulation of starfish oocytes and their following interaction with spermatozoa induce rapid changes of F-actin and Ca{sup 2+} increases which are prerequisites for normal fertilization and development. Fully grown oocytes isolated from the gonads of starfish contain a large nucleus (∼60–70 μm) (termed germinal vesicle, GV), which is arrested at the first prophase of meiosis. If inseminated, these immature oocytes are penetrated by additional spermatozoa. However, starfish oocytes naturally shed into the sea have already initiated the (meiotic) maturation and are normally fertilized between GV breakdown and the extrusion of the first polar body. This is considered the optimum period to ensure monospermic instead of polyspermic fertilization. By contrast, sea urchin eggs are fertilized only after being fully matured, i.e., at the end of the two meiotic divisions. Here, we provide a comparative review of the role of the actin cytoskeleton in oocyte maturation and fertilization in starfish and sea urchin. It has become increasingly evident that the exquisite regulation of the cortical F-actin is involved in nearly all aspects of the molecular events taking place during the progression of meiotic maturation and fertilization.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

The galectin LEC-5 is a novel binding partner for RAB-11

RAB-11/Rab11 is an endosomal GTPase with conserved roles in directional trafficking and apical domain formation in polarized epithelial cells. From a yeast two-hybrid screen using full-length C. elegans RAB-11 as bait, we identified LEC-5 as a novel binding protein for RAB-11. LEC-5 is an ortholog of mammalian Galectin-9 which associates with glycosphingolipids and is implicated in apical cargo sorting. We further confirmed the interaction between RAB-11 and LEC-5 via GST-pull down, co-immunoprecipitation and bimolecular fluorescence complementation. In addition, we showed that LEC-5 binds to RAB-11 with its C-terminus. Our results indicate a novel role of RAB-11 in apical sorting via LEC-5. Such a role would extend RAB-11's function as a master regulator of apical trafficking and suggest it could translate apical sorting signals into apical vesicle directionality.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

PACS-1 and adaptor protein-1 mediate ACTH trafficking to the regulated secretory pathway

Highlights: • PACS-1 and AP-1 play critical roles in targeting ACTH to the regulated secretory pathway. • PACS-1 and AP-1 promote the intracellular storage of ACTH. • In the absence of PACS-1 and AP-1, ACTH is constitutively secreted. • PACS-1 localizes to ACTH-positive vesicles in an AP-1-dependent manner. The regulated secretory pathway is a specialized form of protein secretion found in endocrine and neuroendocrine cell types. Pro-opiomelanocortin (POMC) is a pro-hormone that utilizes this pathway to be trafficked to dense core secretory granules (DCSGs). Within this organelle, POMC is processed to multiple bioactive hormones that play key roles in cellular physiology. However, the complete set of cellular membrane trafficking proteins that mediate the correct sorting of POMC to DCSGs remain unknown. Here, we report the roles of the phosphofurin acidic cluster sorting protein – 1 (PACS-1) and the clathrin adaptor protein 1 (AP-1) in the targeting of POMC to DCSGs. Upon knockdown of PACS-1 and AP-1, POMC is readily secreted into the extracellular milieu and fails to be targeted to DCSGs.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Dual arginine recognition of LRRK2 phosphorylated Rab GTPases

Parkinson’s-disease-associated LRRK2 is a multidomain Ser/Thr kinase that phosphorylates a subset of Rab GTPases to control their effector functions. Rab GTPases are the prime regulators of membrane trafficking in eukaryotic cells. Rabs exert their biological effects by recruitment of effector proteins to subcellular compartments via their Rab-binding domain (RBD). Effectors are modular and typically contain additional domains that regulate various aspects of vesicle formation, trafficking, fusion, and organelle dynamics. The RBD of effectors is typically an α-helical coiled coil that recognizes the GTP conformation of the switch 1 and switch 2 motifs of Rabs. LRRK2 phosphorylates Rab8a at T72 (pT72) of its switch 2 α-helix. This post-translational modification enables recruitment of RILPL2, an effector that regulates ciliogenesis in model cell lines. A newly identified RBD motif of RILPL2, termed the X-cap, has been shown to recognize the phosphate via direct interactions between an arginine residue (R132) and pT72 of Rab8a. Here, we show that a second distal arginine (R130) is also essential for phospho-Rab binding by RILPL2. Through structural, biophysical, and cellular studies, we find that R130 stabilizes the primary R132:pT72 salt bridge through favorable enthalpic contributions to the binding affinity. These findings may have implications for the mechanism by which LRRK2 activation leads to assembly of phospho-Rab complexes and subsequent control of their membrane trafficking functions in cells.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2019

cindr, the Drosophila Homolog of the CD2AP Alzheimer's Disease Risk Gene, Is Required for Synaptic Transmission and Proteostasis

The Alzheimer’s disease (AD) susceptibility gene, CD2-associated protein (CD2AP), encodes an actin binding adaptor protein, but its function in the nervous system is largely unknown. Loss of the Drosophila ortholog cindr enhances neurotoxicity of human Tau, which forms neurofibrillary tangle pathology in AD. We show that Cindr is expressed in neurons and present at synaptic terminals. cindr mutants show impairments in synapse maturation and both synaptic vesicle recycling and release. Cindr associates and genetically interacts with 14-3-3?, regulates the ubiquitin-proteasome system, and affects turnover of Synapsin and the plasma membrane calcium ATPase (PMCA). Loss of cindr elevates PMCA levels and reduces cytosolic calcium. Studies of Cd2ap null mice support a conserved role in synaptic proteostasis, and CD2AP protein levels are inversely related to Synapsin abundance in human postmortem brains. Our results reveal CD2AP neuronal requirements with relevance to AD susceptibility, including for proteostasis, calcium handling, and synaptic structure and function.

Alzheimer's disease, risk gene, cindr, Drosophila,↗