Tetraspanin 6: A novel regulator of hippocampal synaptic transmission and long term plasticity

Tetraspanins (Tspan) are transmembrane proteins with important scaffold and signalling functions. Deletions of Tetraspanin 6 (Tspan6) gene, a member of the tetraspanin family, have been reported in patients with Epilepsy Female-restricted with Mental Retardation (EFMR). Interestingly, mutations in Tspan7, highly homologous to Tspan6, are associated with X-linked intellectual disability, suggesting that these two proteins are important for cognition. Considering recent evidences showing that Tspan7 plays a key role in synapse development and AMPAR trafficking, we initiated the study of Tspan6 in synaptic function using a Tspan6 knock out mouse model. Here we report that hippocampal field recordings from Tspan6 knock out mice show an enhanced basal synaptic transmission and impaired long term potentiation (LTP). A normal paired-pulse facilitation response suggests that Tspan6 affects the properties of the postsynaptic rather than the presynaptic terminal. However, no changes in spine morphology or postsynaptic markers could be detected in Tspan6 KO mice compared with wild types. In addition, Tspan6 KO mice show normal locomotor behaviour and no defects in hippocampus-dependent memory tests

Correction: Tetraspanin 6: A novel regulator of hippocampal synaptic transmission and long term plasticity

[This corrects the article DOI: 10.1371/journal.pone.0171968.]

Tetraspanin 6: a pivotal protein of the multiple vesicular body determining exosome release and lysosomal degradation of amyloid precursor protein fragments

BACKGROUND: The mechanisms behind Aβ-peptide accumulation in non-familial Alzheimer’s disease (AD) remain elusive. Proteins of the tetraspanin family modulate Aβ production by interacting to γ-secretase. METHODS: We searched for tetraspanins with altered expression in AD brains. The function of the selected tetraspanin was studied in vitro and the physiological relevance of our findings was confirmed in vivo. RESULTS: Tetraspanin-6 (TSPAN6) is increased in AD brains and overexpression in cells exerts paradoxical effects on Amyloid Precursor Protein (APP) metabolism, increasing APP-C-terminal fragments (APP-CTF) and Aβ levels at the same time. TSPAN6 affects autophagosome-lysosomal fusion slowing down the degradation of APP-CTF. TSPAN6 recruits also the cytosolic, exosome-forming adaptor syntenin which increases secretion of exosomes that contain APP-CTF. CONCLUSIONS: TSPAN6 is a key player in the bifurcation between lysosomal-dependent degradation and exosome mediated secretion of APP-CTF. This corroborates the central role of the autophagosomal/lysosomal pathway in APP metabolism and shows that TSPAN6 is a crucial player in APP-CTF turnover

Structural analysis on mutation residues and interfacial water molecules for human TIM disease understanding

10.1186/1471-2105-14-S16-S11BMC Bioinformatics14SUPPL16-BBMI

Protective Effect of Tetrahydroxystilbene Glucoside on 6-OHDA-Induced Apoptosis in PC12 Cells through the ROS-NO Pathway

Oxidative stress plays an important role in the pathogenesis of neurodegenerative diseases, such as Parkinson's disease. The molecule, 2,3,5,4′-tetrahydr- oxystilbene-2-O-β-D-glucoside (TSG), is a potent antioxidant derived from the Chinese herb, Polygonum multiflorum Thunb. In this study, we investigated the protective effect of TSG against 6-hydroxydopamine-induced apoptosis in rat adrenal pheochromocytoma PC12 cells and the possible mechanisms. Our data demonstrated that TSG significantly reversed the 6-hydroxydopamine-induced decrease in cell viability, prevented 6-hydroxydopamine-induced changes in condensed nuclei and decreased the percentage of apoptotic cells in a dose-dependent manner. In addition, TSG slowed the accumulation of intracellular reactive oxygen species and nitric oxide, counteracted the overexpression of inducible nitric oxide syntheses as well as neuronal nitric oxide syntheses, and also reduced the level of protein-bound 3-nitrotyrosine. These results demonstrate that the protective effects of TSG on rat adrenal pheochromocytoma PC12 cells are mediated, at least in part, by the ROS-NO pathway. Our results indicate that TSG may be effective in providing protection against neurodegenerative diseases associated with oxidative stress

Neuronal lysosomal dysfunction releases exosomes harboring APP C-terminal fragments and unique lipid signatures

Defects in endolysosomal and autophagic functions are increasingly viewed as key pathological features of neurodegenerative disorders. A master regulator of these functions is phosphatidylinositol-3-phosphate (PI3P), a phospholipid synthesized primarily by class III PI 3-kinase Vps34. Here we report that disruption of neuronal Vps34 function in vitro and in vivo impairs autophagy, lysosomal degradation as well as lipid metabolism, causing endolysosomal membrane damage. PI3P deficiency also promotes secretion of unique exosomes enriched for undigested lysosomal substrates, including amyloid precursor protein C-terminal fragments (APP-CTFs), specific sphingolipids, and the phospholipid bis(monoacylglycero)phosphate (BMP), which normally resides in the internal vesicles of endolysosomes. Secretion of these exosomes requires neutral sphingomyelinase 2 and sphingolipid synthesis. Our results reveal a homeostatic response counteracting lysosomal dysfunction via secretion of atypical exosomes eliminating lysosomal waste and define exosomal APP-CTFs and BMP as candidate biomarkers for endolysosomal dysfunction associated with neurodegenerative disorders.Fan Wang for the kind gift of the Pi3kc3flox/flox mice. We thank Basant Abdulrahman and Hermann Schaetzl for providing the gene-edited Atg5 KO N2a cells. We are also grateful to Zhenyu Yue, Ralph Nixon, and Jean Gruenberg for the kind gift of anti-Atg14L, Cathepsin D, and BMP antibodies, respectively. We thank Thomas Südhof for sharing Cre recombinase lentiviruses. We thank the OCS Microscopy Core of New York University Langone Medical Center for the support of the EM work and Rocio Perez-Gonzalez and Efrat Levy of New York University for their support during optimization of the brain exosome isolation technique. We thank Elizabeta Micevska for the maintenance and genotyping of the animal colony and Bowen Zhou for the preliminary lipidomic analysis of conditional Pi3kc3 cKO mice. We also thank Rebecca Williams and Catherine Marquer for critically reading the manuscript. This work was supported by grants from the Fundação para a Ciência e Tecnologia (PD/BD/105915/2014 to A.M.M.); the National Institute of Health (R01 NS056049 to G.D.P., transferred to Ron Liem, Columbia University; T32-MH015174 to Rene Hen (Z.M.L.)). Z.M.L. and R.B.C. received pilot grants from ADRC grant P50 AG008702 to S.A.S.info:eu-repo/semantics/publishedVersio

Mechanism of nitrogen metabolism-related parameters and enzyme activities in the pathophysiology of autism

<p>Abstract</p> <p>Background</p> <p>There is evidence that impaired metabolism play an important role in the etiology of many neuropsychiatric disorders. Although this has not been investigated to date, several recent studies proposed that nitrogen metabolism-related parameters may have a pathophysiological role in autism.</p> <p>Methods</p> <p>The study enrolled 20 Saudi boys with autism aged 4 to 12 years and 20 healthy controls matched for age and gender. Levels of creatine, urea, ammonia, gamma-aminobutyric acid (GABA), glutamate:glutamine (Glu:Gln) ratio, and enzymatic activities of glutamate dehydrogenase, 5'-nucleotidase, and adenosine deaminase (ADA) were determined in plasma samples from both groups.</p> <p>Results</p> <p>We found a significant elevation of creatine, 5'-nucleotidase, GABA, and glutamic acid and a significant decrease in the enzymatic activity of ADA and glutamine level in patients with autism compared with healthy controls. The most significant variation between the two groups was found in the Glu:Gln ratio.</p> <p>Conclusion</p> <p>A raised Glu:Gln ratio together with positive correlations in creatine, GABA, and 5'-nucleotidase levels could contribute to the pathophysiology of autism, and might be useful diagnostic markers. The mechanism through which these parameters might be related to autism is discussed in detail.</p

Early and reversible changes to the hippocampal proteome in mice on a high-fat diet

Funding LMW, FMC, CG, ACM and C-DM were funded by the Scottish Government’s Rural and Environment Science and Analytical Services Division (RESAS). FHM was supported by an EASTBIO DTP BBSRC studentship. DS was supported by a SULSA studentship.Peer reviewedPublisher PD