Recent Submissions

  • Journal Article

    Judgments of effort exerted by others are influenced by received rewards 

    Rollwage, Max; Pannach, Franziska; Stinson, Caedyn; Toelch, Ulf; Kagan, Igor; Pooresmaeili, Arezoo
    Scientific Reports 2020; 10(1) p.1-14: Art. 1868
    Estimating invested effort is a core dimension for evaluating own and others’ actions, and views on the relationship between effort and rewards are deeply ingrained in various societal attitudes. Internal representations of effort, however, are inherently noisy, e.g. due to the variability of sensorimotor and visceral responses to physical exertion. The uncertainty in effort judgments is further aggravated when there is no direct access to the internal representations of exertion – such as when estimating the effort of another person. Bayesian cue integration suggests that this uncertainty can be resolved by incorporating additional cues that are predictive of effort, e.g. received rewards. We hypothesized that judgments about the effort spent on a task will be influenced by the magnitude of received rewards. Additionally, we surmised that such influence might further depend on individual beliefs regarding the relationship between hard work and prosperity, as exemplified by a conservative work ethic. To test these predictions, participants performed an effortful task interleaved with a partner and were informed about the obtained reward before rating either their own or the partner’s effort. We show that higher rewards led to higher estimations of exerted effort in self-judgments, and this effect was even more pronounced for other-judgments. In both types of judgment, computational modelling revealed that reward information and sensorimotor markers of exertion were combined in a Bayes-optimal manner in order to reduce uncertainty. Remarkably, the extent to which rewards influenced effort judgments was associated with conservative world-views, indicating links between this phenomenon and general beliefs about the relationship between effort and earnings in society.
    View Document Abstract
  • Journal Article

    Endophilin-A coordinates priming and fusion of neurosecretory vesicles via intersectin 

    Gowrisankaran, Sindhuja; Houy, Sébastien; del Castillo, Johanna G. Peña; Steubler, Vicky; Gelker, Monika; Kroll, Jana; Pinheiro, Paulo S.; Schwitters, Dirk; Halbsgut, Nils; Pechstein, Arndt; et al.
    van Weering, Jan R. T.Maritzen, TanjaHaucke, VolkerRaimundo, NunoSørensen, Jakob B.Milosevic, Ira
    Nature Communications 2020; 11(1) p.1-18: Art. 1266
    Endophilins-A are conserved endocytic adaptors with membrane curvature-sensing and -inducing properties. We show here that, independently of their role in endocytosis, endophilin-A1 and endophilin-A2 regulate exocytosis of neurosecretory vesicles. The number and distribution of neurosecretory vesicles were not changed in chromaffin cells lacking endophilin-A, yet fast capacitance and amperometry measurements revealed reduced exocytosis, smaller vesicle pools and altered fusion kinetics. The levels and distributions of the main exocytic and endocytic factors were unchanged, and slow compensatory endocytosis was not robustly affected. Endophilin-A’s role in exocytosis is mediated through its SH3-domain, specifically via a direct interaction with intersectin-1, a coordinator of exocytic and endocytic traffic. Endophilin-A not able to bind intersectin-1, and intersectin-1 not able to bind endophilin-A, resulted in similar exocytic defects in chromaffin cells. Altogether, we report that two endocytic proteins, endophilin-A and intersectin-1, are enriched on neurosecretory vesicles and regulate exocytosis by coordinating neurosecretory vesicle priming and fusion.
    View Document Abstract
  • Journal Article

    Dose-dependent effect of cannabinoid WIN-55,212-2 on myelin repair following a demyelinating insult 

    Tomas-Roig, J.; Agbemenyah, H. Y.; Celarain, N.; Quintana, E.; Ramió-Torrentà, Ll.; Havemann-Reinecke, U.
    Scientific Reports 2020; 10(1): Art. 590
    Dysfunctions in the endocannabinoid system have been associated with experimental animal models and multiple sclerosis patients. Interestingly, the endocannabinoid system has been reported to confer neuroprotection against demyelination. The present study aims to assess the effects of the cannabinoid agonist WIN-55,212-2 in cuprizone fed animals on myelin repair capacity. Animals exposed to cuprizone were simultaneously treated withWIN-55,212-2, behaviorally tested and finally the corpus callosum was exhaustively studied by Western blotting, qRT-PCR and a myelin staining procedure. We report that the long-term administration of WIN-55,212-2 reduced the global amount of CB1 protein. Histological analysis revealed clear demyelination after being fed cuprizone for three weeks. However, cuprizone-fed mice subjected to 0.5 mg/Kg of WIN-55,212-2 displayed no differences when compared to controls during demyelination, although there was a robust increase in the myelinated axons during the remyelination phase. These animals displayed better performance on contextual fear conditioning which was in turn non-attributable to an antinociceptive effect. In contrast, a 1 mg/Kg dosage caused a remarkable demyelination accompanied by limited potential for myelin repair. Upon drug administration while mice ongoing demyeliniation, the expression of Aif1 (microglia) and Gfap (astrocytes) followed a dose-dependent manner whereas the expression of both markers was apparently attenuated during remyelination. Treatment with vehicle or 0.5 mg/Kg of the drug during demyelination increased the expression of Pdgfra (oligodendrocyte precursor cells) but this did not occur when 1 mg/Kg was administered. In conclusion, the drug at 0.5 mg/Kg did not alter myelin architecture while 1 mg/Kg had a deleterious effect in this model.
    View Document Abstract
  • Journal Article

    Integrated Analyses of Microbiome and Longitudinal Metabolome Data Reveal Microbial-Host Interactions on Sulfur Metabolism in Parkinson’s Disease 

    Hertel, Johannes; Harms, Amy C.; Heinken, Almut; Baldini, Federico; Thinnes, Cyrille C.; Glaab, Enrico; Vasco, Daniel A.; Pietzner, Maik; Stewart, Isobel D.; Wareham, Nicholas J.; et al.
    Langenberg, ClaudiaTrenkwalder, ClaudiaKrüger, RejkoHankemeier, ThomasFleming, Ronan M.T.Mollenhauer, BritThiele, Ines
    Cell Reports 2019; 29(7): Art. 1777.e8
    Parkinson's disease (PD) exhibits systemic effects on the human metabolism, with emerging roles for the gut microbiome. Here, we integrate longitudinal metabolome data from 30 drug-naive, de novo PD patients and 30 matched controls with constraint-based modeling of gut microbial communities derived from an independent, drug-naive PD cohort, and prospective data from the general population. Our key results are (1) longitudinal trajectory of metabolites associated with the interconversion of methionine and cysteine via cystathionine differed between PD patients and controls; (2) dopaminergic medication showed strong lipidomic signatures; (3) taurine-conjugated bile acids correlated with the severity of motor symptoms, while low levels of sulfated taurolithocholate were associated with PD incidence in the general population; and (4) computational modeling predicted changes in sulfur metabolism, driven by A. muciniphila and B. wadsworthia, which is consistent with the changed metabolome. The multi-omics integration reveals PD-specific patterns in microbial-host sulfur co-metabolism that may contribute to PD severity.
    View Document Abstract
  • Journal Article

    Subcellular Targeting of VIP Boutons in Mouse Barrel Cortex is Layer-Dependent and not Restricted to Interneurons 

    Zhou, Xiaojuan; Rickmann, Michael; Hafner, Georg; Staiger, Jochen F.
    Cerebral Cortex 2017; 27(11) p.5353-5368
    Neocortical vasoactive intestinal polypeptide (VIP) expressing cells are a diverse subpopulation of GABAergic interneurons issuing distinct axonal projections. They are known to inhibit other types of interneurons as well as excitatory principal neurons and possess a disinhibitory net effect in cortical circuits. In order to elucidate their targeting specificity, the output connectivity of VIP interneurons was studied at the subcellular level in barrel cortex of interneuron-specific Cre-driver mice, using pre- and postembedding electron microscopy. Systematically sampling VIP boutons across all layers, we found a substantial proportion of the innervated subcellular structures were dendrites (80%), with somata (13%), and spines (7%) being much less targeted. In layer VI, a high proportion of axosomatic synapses was found (39%). GABA-immunopositive ratio was quantified among the targets using statistically validated thresholds: only 37% of the dendrites, 7% of the spines, and 26% of the somata showed above-threshold immunogold labeling. For the main target structure "dendrite", a higher proportion of GABAergic subcellular profiles existed in deep than in superficial layers. In conclusion, VIP interneurons innervate non-GABAergic excitatory neurons and interneurons at their subcellular domains with layer-dependent specificity. This suggests a diverse output of VIP interneurons, which predicts multiple functionality in cortical circuitry beyond disinhibition.
    View Document Abstract
  • Journal Article

    Efficacy of venlafaxine extended release in major depressive disorder patients 

    Lyndon, Gavin J.; Prieto, Rita; Wajsbrot, Dalia B.; Allgulander, Christer; Bandelow, Borwin
    International Clinical Psychopharmacology 2019; 34(3) p.110-118
    Effects of baseline anxiety on the efficacy of venlafaxine extended release versus placebo were examined in a post hoc pooled subgroup analysis of 1573 patients enrolled in eight short-term studies of major depressive disorder. Anxiety subgroups were defined based on baseline 17-item Hamilton Rating Scale for Depression Item 10 score <3 (low) versus ≥3 (high). Change from baseline to final visit in Montgomery-Åsberg Depression Rating Scale total score and Montgomery-Åsberg Depression Rating Scale response and remission rates were analyzed. Change from baseline in Montgomery-Åsberg Depression Rating Scale total score and response and remission rates was significantly greater for venlafaxine extended release versus placebo in both low and high anxiety subgroups (all P < 0.0001). A statistically significant baseline anxiety by treatment interaction was observed for Montgomery-Åsberg Depression Rating Scale total score only (P = 0.0152). The adjusted mean change from baseline in Montgomery-Åsberg Depression Rating Scale total score was significantly greater in the high anxiety subgroup versus low anxiety subgroup for patients treated with venlafaxine extended release (-6.27 versus -3.89; P = 0.0440) but not placebo. These results support the efficacy of venlafaxine extended release for major depressive disorder treatment in patients with anxiety symptoms.
    View Document Abstract
  • Journal Article

    Intracranial mechanical thrombectomy of large vessel occlusions in the posterior circulation using SAVE 

    Maus, Volker; Styczen, Hanna; Liman, Jan; Maier, Ilko; Brehm, Alex; Tsogkas, Ioannis; Psychogios, Marios-Nikos
    BMC Neurology 2019; 19(1): Art. 197
    BACKGROUND: Mechanical thrombectomy (MT) using stent retriever assisted vacuum-locked extraction (SAVE) is a promising method for anterior circulation strokes. We present our experience with SAVE for large vessel occlusions (LVO) of the posterior circulation. METHODS: We retrospectively analyzed 66 consecutive MT patients suffering from LVO of the posterior circulation. Primary endpoints were first-pass and overall complete/near complete reperfusion, defined as a modified thrombolysis in cerebral infarction (mTICI) score of 2c and 3. Secondary endpoints contained number of passes, time interval from groin puncture to reperfusion and rate of postinterventional symptomatic intracranial hemorrhage (sICH). RESULTS: Median age was 75 years (interquartile range (IQR) 54-81 years). Baseline median National Institutes of Health stroke scale (NIHSS) was 13 (IQR 8-21). Fifty-five (83%) patients had LVO of the basilar artery and 11 (17%) of the posterior cerebral artery. Eighteen (27%) patients were treated with SAVE and 21 (32%) with aspiration only. First pass mTICI2c or 3 and overall mTICI2c or 3 were documented in 11/18 (61%) and 14/18 (78%) with SAVE and in 4/21 (19%) and 13/21 (33%) with aspiration only. Median attempt was 1 (IQR 1-2) with SAVE and 2 (IQR 1-4) with aspiration (p = 0.0249). Median groin to reperfusion time did not differ significantly between groups. The rate of sICH was 5% without any complications in the SAVE cohort. CONCLUSION: Mechanical thrombectomy of posterior large vessel occlusions with SAVE is feasible, safe, and effective with high rates of near-complete and complete reperfusion.
    View Document Abstract
  • Journal Article

    Cation selectivity of the presequence translocase channel Tim23 is crucial for efficient protein import 

    Denkert, Niels; Schendzielorz, Alexander Benjamin; Barbot, Mariam; Versemann, Lennart; Richter, Frank; Rehling, Peter; Meinecke, Michael
    eLife 2017; 6: Art. eLife.28324
    Virtually all mitochondrial matrix proteins and a considerable number of inner membrane proteins carry a positively charged, N-terminal presequence and are imported by the TIM23 complex (presequence translocase) located in the inner mitochondrial membrane. The voltage-regulated Tim23 channel constitutes the actual protein-import pore wide enough to allow the passage of polypeptides with a secondary structure. In this study, we identify amino acids important for the cation selectivity of Tim23. Structure based mutants show that selectivity is provided by highly conserved, pore-lining amino acids. Mutations of these amino acid residues lead to reduced selectivity properties, reduced protein import capacity and they render the Tim23 channel insensitive to substrates. We thus show that the cation selectivity of the Tim23 channel is a key feature for substrate recognition and efficient protein import.
    View Document Abstract
  • Journal Article

    Mitochondrial respiratory chain deficiency inhibits lysosomal hydrolysis 

    Fernandez-Mosquera, Lorena; Yambire, King Faisal; Couto, Renata; Pereyra, Leonardo; Pabis, Kamil; Ponsford, Amy H.; Diogo, Cátia V.; Stagi, Massimiliano; Milosevic, Ira; Raimundo, Nuno
    Autophagy(27) p.1-20
    Mitochondria are key organelles for cellular metabolism, and regulate several processes including cell death and macroautophagy/autophagy. Here, we show that mitochondrial respiratory chain (RC) deficiency deactivates AMP-activated protein kinase (AMPK, a key regulator of energy homeostasis) signaling in tissue and in cultured cells. The deactivation of AMPK in RC-deficiency is due to increased expression of the AMPK-inhibiting protein FLCN (folliculin). AMPK is found to be necessary for basal lysosomal function, and AMPK deactivation in RC-deficiency inhibits lysosomal function by decreasing the activity of the lysosomal Ca2+ channel MCOLN1 (mucolipin 1). MCOLN1 is regulated by phosphoinositide kinase PIKFYVE and its product PtdIns(3,5)P2, which is also decreased in RC-deficiency. Notably, reactivation of AMPK, in a PIKFYVE-dependent manner, or of MCOLN1 in RC-deficient cells, restores lysosomal hydrolytic capacity. Building on these data and the literature, we propose that downregulation of the AMPK-PIKFYVE-PtdIns(3,5)P2-MCOLN1 pathway causes lysosomal Ca2+ accumulation and impaired lysosomal catabolism. Besides unveiling a novel role of AMPK in lysosomal function, this study points to the mechanism that links mitochondrial malfunction to impaired lysosomal catabolism, underscoring the importance of AMPK and the complexity of organelle cross-talk in the regulation of cellular homeostasis. Abbreviation: ΔΨm: mitochondrial transmembrane potential; AMP: adenosine monophosphate; AMPK: AMP-activated protein kinase; ATG5: autophagy related 5; ATP: adenosine triphosphate; ATP6V0A1: ATPase, H+ transporting, lysosomal, V0 subbunit A1; ATP6V1A: ATPase, H+ transporting, lysosomal, V0 subbunit A; BSA: bovine serum albumin; CCCP: carbonyl cyanide-m-chlorophenylhydrazone; CREB1: cAMP response element binding protein 1; CTSD: cathepsin D; CTSF: cathepsin F; DMEM: Dulbecco's modified Eagle's medium; DMSO: dimethyl sulfoxide; EBSS: Earl's balanced salt solution; ER: endoplasmic reticulum; FBS: fetal bovine serum; FCCP: carbonyl cyanide-p-trifluoromethoxyphenolhydrazone; GFP: green fluorescent protein; GPN: glycyl-L-phenylalanine 2-naphthylamide; LAMP1: lysosomal associated membrane protein 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MCOLN1/TRPML1: mucolipin 1; MEF: mouse embryonic fibroblast; MITF: melanocyte inducing transcription factor; ML1N*2-GFP: probe used to detect PtdIns(3,5)P2 based on the transmembrane domain of MCOLN1; MTORC1: mechanistic target of rapamycin kinase complex 1; NDUFS4: NADH:ubiquinone oxidoreductase subunit S4; OCR: oxygen consumption rate; PBS: phosphate-buffered saline; pcDNA: plasmid cytomegalovirus promoter DNA; PCR: polymerase chain reaction; PtdIns3P: phosphatidylinositol-3-phosphate; PtdIns(3,5)P2: phosphatidylinositol-3,5-bisphosphate; PIKFYVE: phosphoinositide kinase, FYVE-type zinc finger containing; P/S: penicillin-streptomycin; PVDF: polyvinylidene fluoride; qPCR: quantitative real time polymerase chain reaction; RFP: red fluorescent protein; RNA: ribonucleic acid; SDS-PAGE: sodium dodecyl sulfate polyacrylamide gel electrophoresis; shRNA: short hairpin RNA; siRNA: small interfering RNA; TFEB: transcription factor EB; TFE3: transcription factor binding to IGHM enhancer 3; TMRM: tetramethylrhodamine, methyl ester, perchlorate; ULK1: unc-51 like autophagy activating kinase 1; ULK2: unc-51 like autophagy activating kinase 2; UQCRC1: ubiquinol-cytochrome c reductase core protein 1; v-ATPase: vacuolar-type H+-translocating ATPase; WT: wild-type.
    View Document Abstract
  • Journal Article

    Medial prefrontal cortex supports perceptual memory 

    Schwiedrzik, Caspar M.; Sudmann, Sandrin S.; Thesen, Thomas; Wang, Xiuyuan; Groppe, David M.; Mégevand, Pierre; Doyle, Werner; Mehta, Ashesh D.; Devinsky, Orrin; Melloni, Lucia
    Current Biology 2018; 28(18) p.R1094-R1095
    View Document
  • Journal Article

    IgSF9b regulates anxiety behaviors through effects on centromedial amygdala inhibitory synapses 

    Babaev, Olga; Cruces-Solis, Hugo; Piletti Chatain, Carolina; Hammer, Matthieu; Wenger, Sally; Ali, Heba; Karalis, Nikolaos; de Hoz, Livia; Schlüter, Oliver M.; Yanagawa, Yuchio; et al.
    Ehrenreich, HanneloreTaschenberger, HolgerBrose, NilsKrueger-Burg, Dilja
    Nature Communications 2018; 9(1): Art. 5400
    Abnormalities in synaptic inhibition play a critical role in psychiatric disorders, and accordingly, it is essential to understand the molecular mechanisms linking components of the inhibitory postsynapse to psychiatrically relevant neural circuits and behaviors. Here we study the role of IgSF9b, an adhesion protein that has been associated with affective disorders, in the amygdala anxiety circuitry. We show that deletion of IgSF9b normalizes anxiety-related behaviors and neural processing in mice lacking the synapse organizer Neuroligin-2 (Nlgn2), which was proposed to complex with IgSF9b. This normalization occurs through differential effects of Nlgn2 and IgSF9b at inhibitory synapses in the basal and centromedial amygdala (CeM), respectively. Moreover, deletion of IgSF9b in the CeM of adult Nlgn2 knockout mice has a prominent anxiolytic effect. Our data place IgSF9b as a key regulator of inhibition in the amygdala and indicate that IgSF9b-expressing synapses in the CeM may represent a target for anxiolytic therapies.
    View Document Abstract
  • Journal Article

    Mitochondrial biogenesis is transcriptionally repressed in lysosomal lipid storage diseases 

    Yambire, King Faisal; Fernandez-Mosquera, Lorena; Steinfeld, Robert; Mühle, Christiane; Ikonen, Elina; Milosevic, Ira; Raimundo, Nuno
    eLife 2019; 8: Art. e39598
    Perturbations in mitochondrial function and homeostasis are pervasive in lysosomal storage diseases, but the underlying mechanisms remain unknown. Here, we report a transcriptional program that represses mitochondrial biogenesis and function in lysosomal storage diseases Niemann-Pick type C (NPC) and acid sphingomyelinase deficiency (ASM), in patient cells and mouse tissues. This mechanism is mediated by the transcription factors KLF2 and ETV1, which are both induced in NPC and ASM patient cells. Mitochondrial biogenesis and function defects in these cells are rescued by the silencing of KLF2 or ETV1. Increased ETV1 expression is regulated by KLF2, while the increase of KLF2 protein levels in NPC and ASM stems from impaired signaling downstream sphingosine-1-phosphate receptor 1 (S1PR1), which normally represses KLF2. In patient cells, S1PR1 is barely detectable at the plasma membrane and thus unable to repress KLF2. This manuscript provides a mechanistic pathway for the prevalent mitochondrial defects in lysosomal storage diseases. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).
    View Document Abstract
  • Journal Article

    Investigating the feasibility of channelrhodopsin variants for nanoscale optogenetics 

    Stahlberg, Markus A.; Ramakrishnan, Charu; Willig, Katrin I.; Boyden, Edward S.; Deisseroth, Karl; Dean, Camin
    Neurophotonics 2019; 6(1): Art. 015007
    Optogenetics has revolutionized the study of circuit function in the brain, by allowing activation of specific ensembles of neurons by light. However, this technique has not yet been exploited extensively at the subcellular level. Here, we test the feasibility of a focal stimulation approach using stimulated emission depletion/reversible saturable optical fluorescence transitions-like illumination, whereby switchable light-gated channels are focally activated by a laser beam of one wavelength and deactivated by an overlapping donut-shaped beam of a different wavelength, confining activation to a center focal region. This method requires that activated channelrhodopsins are inactivated by overlapping illumination of a distinct wavelength and that photocurrents are large enough to be detected at the nanoscale. In tests of current optogenetic tools, we found that ChR2 C128A/H134R/T159C and CoChR C108S and C108S/D136A-activated with 405-nm light and inactivated by coillumination with 594-nm light-and C1V1 E122T/C167S-activated by 561-nm light and inactivated by 405-nm light-were most promising in terms of highest photocurrents and efficient inactivation with coillumination. Although further engineering of step-function channelrhodopsin variants with higher photoconductances will be required to employ this approach at the nanoscale, our findings provide a framework to guide future development of this technique.
    View Document Abstract
  • Journal Article

    An opposing function of paralogs in balancing developmental synapse maturation. 

    Favaro, Plinio D.; Huang, Xiaojie; Hosang, Leon; Stodieck, Sophia; Cui, Lei; Liu, Yu-Zhang; Engelhardt, Karl-Alexander; Schmitz, Frank; Dong, Yan; Löwel, Siegrid; et al.
    Schlüter, Oliver M.
    PLOS Biology 2018; 16(12): Art. e2006838
    The disc-large (DLG)-membrane-associated guanylate kinase (MAGUK) family of proteins forms a central signaling hub of the glutamate receptor complex. Among this family, some proteins regulate developmental maturation of glutamatergic synapses, a process vulnerable to aberrations, which may lead to neurodevelopmental disorders. As is typical for paralogs, the DLG-MAGUK proteins postsynaptic density (PSD)-95 and PSD-93 share similar functional domains and were previously thought to regulate glutamatergic synapses similarly. Here, we show that they play opposing roles in glutamatergic synapse maturation. Specifically, PSD-95 promoted, whereas PSD-93 inhibited maturation of immature α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-type glutamate receptor (AMPAR)-silent synapses in mouse cortex during development. Furthermore, through experience-dependent regulation of its protein levels, PSD-93 directly inhibited PSD-95's promoting effect on silent synapse maturation in the visual cortex. The concerted function of these two paralogs governed the critical period of juvenile ocular dominance plasticity (jODP), and fine-tuned visual perception during development. In contrast to the silent synapse-based mechanism of adjusting visual perception, visual acuity improved by different mechanisms. Thus, by controlling the pace of silent synapse maturation, the opposing but properly balanced actions of PSD-93 and PSD-95 are essential for fine-tuning cortical networks for receptive field integration during developmental critical periods, and imply aberrations in either direction of this process as potential causes for neurodevelopmental disorders.
    View Document Abstract
  • Journal Article

    Membrane binding, internalization, and sorting of alpha-synuclein in the cell 

    Masaracchia, Caterina; Hnida, Marilena; Gerhardt, Ellen; Lopes da Fonseca, Tomás; Villar-Pique, Anna; Branco, Tiago; Stahlberg, Markus A.; Dean, Camin; Fernández, Claudio O.; Milosevic, Ira; et al.
    Outeiro, Tiago F.
    Acta Neuropathologica Communications. 2018 Aug 14;6(1):79
    Alpha-synuclein (aSyn) plays a crucial role in Parkinson’s disease (PD) and other synucleinopathies, since it misfolds and accumulates in typical proteinaceous inclusions. While the function of aSyn is thought to be related to vesicle binding and trafficking, the precise molecular mechanisms linking aSyn with synucleinopathies are still obscure. aSyn can spread in a prion-like manner between interconnected neurons, contributing to the propagation of the pathology and to the progressive nature of synucleinopathies. Here, we investigated the interaction of aSyn with membranes and trafficking machinery pathways using cellular models of PD that are amenable to detailed molecular analyses. We found that different species of aSyn can enter cells and form high molecular weight species, and that membrane binding properties are important for the internalization of aSyn. Once internalized, aSyn accumulates in intracellular inclusions. Interestingly, we found that internalization is blocked in the presence of dynamin inhibitors (blocked membrane scission), suggesting the involvement of the endocytic pathway in the internalization of aSyn. By screening a pool of small Rab-GTPase proteins (Rabs) which regulate membrane trafficking, we found that internalized aSyn partially colocalized with Rab5A and Rab7. Initially, aSyn accumulated in Rab4A-labelled vesicles and, at later stages, it reached the autophagy-lysosomal pathway (ALP) where it gets degraded. In total, our study emphasizes the importance of membrane binding, not only as part of the normal function but also as an important step in the internalization and subsequent accumulation of aSyn. Importantly, we identified a fundamental role for Rab proteins in the modulation of aSyn processing, clearance and spreading, suggesting that targeting Rab proteins may hold important therapeutic value in PD and other synucleinopathies.
    View Document Abstract
  • Journal Article

    YKL-40 in the brain and cerebrospinal fluid of neurodegenerative dementias 

    Llorens, Franc; Thüne, Katrin; Tahir, Waqas; Kanata, Eirini; Diaz-Lucena, Daniela; Xanthopoulos, Konstantinos; Kovatsi, Eleni; Pleschka, Catharina; Garcia-Esparcia, Paula; Schmitz, Matthias; et al.
    Ozbay, DuruCorreia, SusanaCorreia, ÂngelaMilosevic, IraAndréoletti, OlivierFernández-Borges, NataliaVorberg, Ina M.Glatzel, MarkusSklaviadis, TheodorosTorres, Juan M.Krasemann, SusanneSánchez-Valle, RaquelFerrer, IsidroZerr, Inga
    Molecular Neurodegeneration. 2017 Nov 10;12(1):83
    Background YKL-40 (also known as Chitinase 3-like 1) is a glycoprotein produced by inflammatory, cancer and stem cells. Its physiological role is not completely understood but YKL-40 is elevated in the brain and cerebrospinal fluid (CSF) in several neurological and neurodegenerative diseases associated with inflammatory processes. Yet the precise characterization of YKL-40 in dementia cases is missing. Methods In the present study, we comparatively analysed YKL-40 levels in the brain and CSF samples from neurodegenerative dementias of different aetiologies characterized by the presence of cortical pathology and disease-specific neuroinflammatory signatures. Results YKL-40 was normally expressed in fibrillar astrocytes in the white matter. Additionally YKL-40 was highly and widely expressed in reactive protoplasmic cortical and perivascular astrocytes, and fibrillar astrocytes in sporadic Creutzfeldt-Jakob disease (sCJD). Elevated YKL-40 levels were also detected in Alzheimer’s disease (AD) but not in dementia with Lewy bodies (DLB). In AD, YKL-40-positive astrocytes were commonly found in clusters, often around β-amyloid plaques, and surrounding vessels with β-amyloid angiopathy; they were also distributed randomly in the cerebral cortex and white matter. YKL-40 overexpression appeared as a pre-clinical event as demonstrated in experimental models of prion diseases and AD pathology. CSF YKL-40 levels were measured in a cohort of 288 individuals, including neurological controls (NC) and patients diagnosed with different types of dementia. Compared to NC, increased YKL-40 levels were detected in sCJD (p < 0.001, AUC = 0.92) and AD (p < 0.001, AUC = 0.77) but not in vascular dementia (VaD) (p > 0.05, AUC = 0.71) or in DLB/Parkinson’s disease dementia (PDD) (p > 0.05, AUC = 0.70). Further, two independent patient cohorts were used to validate the increased CSF YKL-40 levels in sCJD. Additionally, increased YKL-40 levels were found in genetic prion diseases associated with the PRNP-D178N (Fatal Familial Insomnia) and PRNP-E200K mutations. Conclusions Our results unequivocally demonstrate that in neurodegenerative dementias, YKL-40 is a disease-specific marker of neuroinflammation showing its highest levels in prion diseases. Therefore, YKL-40 quantification might have a potential for application in the evaluation of therapeutic intervention in dementias with a neuroinflammatory component.
    View Document Abstract
  • Journal Article

    TORC1-mediated sensing of chaperone activity alters glucose metabolism and extends lifespan. 

    Perić, Matea; Lovrić, Anita; Šarić, Ana; Musa, Marina; Bou Dib, Peter; Rudan, Marina; Nikolić, Andrea; Sobočanec, Sandra; Mikecin, Ana-Matea; Dennerlein, Sven; et al.
    Milošević, IraVlahoviček, KristianRaimundo, NunoKriško, Anita
    Aging Cell 2017; 16(5) p.994-1005
    Protein quality control mechanisms, required for normal cellular functioning, encompass multiple functions related to protein production and maintenance. However, the existence of communication between proteostasis and metabolic networks and its underlying mechanisms remain elusive. Here, we report that enhanced chaperone activity and consequent improved proteostasis are sensed by TORC1 via the activity of Hsp82. Chaperone enrichment decreases the level of Hsp82, which deactivates TORC1 and leads to activation of Snf1/AMPK, regardless of glucose availability. This mechanism culminates in the extension of yeast replicative lifespan (RLS) that is fully reliant on both TORC1 deactivation and Snf1/AMPK activation. Specifically, we identify oxygen consumption increase as the downstream effect of Snf1 activation responsible for the entire RLS extension. Our results set a novel paradigm for the role of proteostasis in aging: modulation of the misfolded protein level can affect cellular metabolic features as well as mitochondrial activity and consequently modify lifespan. The described mechanism is expected to open new avenues for research of aging and age-related diseases.
    View Document Abstract
  • Journal Article

    Neurofeedback of Slow Cortical Potentials in Children with Attention-Deficit/Hyperactivity Disorder: A Multicenter Randomized Trial Controlling for Unspecific Effects. 

    Strehl, Ute; Aggensteiner, Pascal; Wachtlin, Daniel; Brandeis, Daniel; Albrecht, Björn; Arana, Maria; Bach, Christiane; Banaschewski, Tobias; Bogen, Thorsten; Flaig-Röhr, Andrea; et al.
    Freitag, Christine M.Fuchsenberger, YvonneGest, StephanieGevensleben, HolgerHerde, LauraHohmann, SarahLegenbauer, TanjaMarx, Anna-MariaMillenet, SabinaPniewski, BenjaminRothenberger, AribertRuckes, ChristianWörz, SonjaHoltmann, Martin
    Frontiers in human neuroscience 2017; 11: Art. 135
    Background: Neurofeedback (NF) in children with attention-deficit/hyperactivity disorder (ADHD) has been investigated in a series of studies over the last years. Previous studies did not unanimously support NF as a treatment in ADHD. Most studies did not control for unspecific treatment effects and did not demonstrate that self-regulation took place. The present study examined the efficacy of NF in comparison to electromyographic (EMG) feedback to control for unspecific effects of the treatment, and assessed self-regulation of slow cortical potentials (SCPs). Methods: A total of 150 children aged 7-9 years diagnosed with ADHD (82% male; 43% medicated) were randomized to 25 sessions of feedback of SCPs (NF) or feedback of coordination of the supraspinatus muscles (EMG). The primary endpoint was the change in parents' ratings of ADHD core symptoms 4 weeks after the end of treatment compared to pre-tests. Results: Children in both groups showed reduced ADHD-core symptoms (NF 0.3, 95% CI -0.42 to -0.18; EMG 0.13, 95% CI -0.26 to -0.01). NF showed a significant superiority over EMG (treatment difference 0.17, 95% CI 0.02-0.3, p = 0.02). This yielded an effect size (ES) of d = 0.57 without and 0.40 with baseline observation carried forward (BOCF). The sensitivity analysis confirmed the primary result. Successful self-regulation of brain activity was observed only in NF. As a secondary result teachers reported no superior improvement from NF compared to EMG, but within-group analysis revealed effects of NF on the global ADHD score, inattention, and impulsivity. In contrast, EMG feedback did not result in changes despite more pronounced self-regulation learning. Conclusions: Based on the primary parent-rated outcome NF proved to be superior to a semi-active EMG feedback treatment. The study supports the feasibility and efficacy of NF in a large sample of children with ADHD, based on both specific and unspecific effects. Trial Register: Current controlled trials ISRCTN76187185, registered 5 February 2009.
    View Document Abstract
  • Journal Article

    The BET/BRD inhibitor JQ1 improves brain plasticity in WT and APP mice. 

    Benito, E.; Ramachandran, B.; Schroeder, H.; Schmidt, G.; Urbanke, H.; Burkhardt, S.; Capece, V.; Dean, C.; Fischer, A.
    Translational psychiatry 2017-09-26; 7(9) p.e1239-e1239
    Histone acetylation is essential for memory formation and its deregulation contributes to the pathogenesis of Alzheimer's disease. Thus, targeting histone acetylation is discussed as a novel approach to treat dementia. The histone acetylation landscape is shaped by chromatin writer and eraser proteins, while readers link chromatin state to cellular function. Chromatin readers emerged novel drug targets in cancer research but little is known about the manipulation of readers in the adult brain. Here we tested the effect of JQ1-a small-molecule inhibitor of the chromatin readers BRD2, BRD3, BRD4 and BRDT-on brain function and show that JQ1 is able to enhance cognitive performance and long-term potentiation in wild-type animals and in a mouse model for Alzheimer's disease. Systemic administration of JQ1 elicited a hippocampal gene expression program that is associated with ion channel activity, transcription and DNA repair. Our findings suggest that JQ1 could be used as a therapy against dementia and should be further tested in the context of learning and memory.
    View Document Abstract
  • Journal Article

    TRPV1 regulates excitatory innervation of OLM neurons in the hippocampus 

    Hurtado-Zavala, Joaquin I.; Ramachandran, Binu; Ahmed, Saheeb; Halder, Rashi; Bolleyer, Christiane; Awasthi, Ankit; Stahlberg, Markus A.; Wagener, Robin J.; Anderson, Kristin; Drenan, Ryan M.; et al.
    Lester, Henry A.Miwa, Julie M.Staiger, Jochen F.Fischer, AndreDean, Camin
    Nature communications 2017; 8: Art. 15878
    TRPV1 is an ion channel activated by heat and pungent agents including capsaicin, and has been extensively studied in nociception of sensory neurons. However, the location and function of TRPV1 in the hippocampus is debated. We found that TRPV1 is expressed in oriens-lacunosum-moleculare (OLM) interneurons in the hippocampus, and promotes excitatory innervation. TRPV1 knockout mice have reduced glutamatergic innervation of OLM neurons. When activated by capsaicin, TRPV1 recruits more glutamatergic, but not GABAergic, terminals to OLM neurons in vitro. When TRPV1 is blocked, glutamatergic input to OLM neurons is dramatically reduced. Heterologous expression of TRPV1 also increases excitatory innervation. Moreover, TRPV1 knockouts have reduced Schaffer collateral LTP, which is rescued by activating OLM neurons with nicotine-via α2β2-containing nicotinic receptors-to bypass innervation defects. Our results reveal a synaptogenic function of TRPV1 in a specific interneuron population in the hippocampus, where it is important for gating hippocampal plasticity.
    View Document Abstract

View more