Publications by authors named "Peter Claus"

92 Publications

A synthetic C4 shuttle via the β-hydroxyaspartate cycle in C3 plants.

Proc Natl Acad Sci U S A 2021 May;118(21)

Institute of Plant Biochemistry, Heinrich Heine University, 40225 Düsseldorf, Germany;

Plants depend on the enzyme ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) for CO fixation. However, especially in C3 plants, photosynthetic yield is reduced by formation of 2-phosphoglycolate, a toxic oxygenation product of Rubisco, which needs to be recycled in a high-flux-demanding metabolic process called photorespiration. Canonical photorespiration dissipates energy and causes carbon and nitrogen losses. Reducing photorespiration through carbon-concentrating mechanisms, such as C4 photosynthesis, or bypassing photorespiration through metabolic engineering is expected to improve plant growth and yield. The β-hydroxyaspartate cycle (BHAC) is a recently described microbial pathway that converts glyoxylate, a metabolite of plant photorespiration, into oxaloacetate in a highly efficient carbon-, nitrogen-, and energy-conserving manner. Here, we engineered a functional BHAC in plant peroxisomes to create a photorespiratory bypass that is independent of 3-phosphoglycerate regeneration or decarboxylation of photorespiratory precursors. While efficient oxaloacetate conversion in still masks the full potential of the BHAC, nitrogen conservation and accumulation of signature C4 metabolites demonstrate the proof of principle, opening the door to engineering a photorespiration-dependent synthetic carbon-concentrating mechanism in C3 plants.
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http://dx.doi.org/10.1073/pnas.2022307118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166194PMC
May 2021

Profilin2 regulates actin rod assembly in neuronal cells.

Sci Rep 2021 May 13;11(1):10287. Epub 2021 May 13.

Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Hannover, Germany.

Nuclear and cytoplasmic actin-cofilin rods are formed transiently under stress conditions to reduce actin filament turnover and ATP hydrolysis. The persistence of these structures has been implicated in disease pathology of several neurological disorders. Recently, the presence of actin rods has been discovered in Spinal Muscular Atrophy (SMA), a neurodegenerative disease affecting predominantly motoneurons leading to muscle weakness and atrophy. This finding underlined the importance of dysregulated actin dynamics in motoneuron loss in SMA. In this study, we characterized actin rods formed in a SMA cell culture model analyzing their composition by LC-MS-based proteomics. Besides actin and cofilin, we identified proteins involved in processes such as ubiquitination, translation or protein folding to be bound to actin rods. This suggests their sequestration to actin rods, thus impairing important cellular functions. Moreover, we showed the involvement of the cytoskeletal protein profilin2 and its upstream effectors RhoA/ROCK in actin rod assembly in SMA. These findings implicate that the formation of actin rods exerts detrimental effects on motoneuron homeostasis by affecting actin dynamics and disturbing essential cellular pathways.
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http://dx.doi.org/10.1038/s41598-021-89397-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119500PMC
May 2021

Impairment of the neurotrophic signaling hub B-Raf contributes to motoneuron degeneration in spinal muscular atrophy.

Proc Natl Acad Sci U S A 2021 May;118(18)

Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Hannover 30625, Germany.

Spinal muscular atrophy (SMA) is a motoneuron disease caused by deletions of the ( and low SMN protein levels. SMN restoration is the concept behind a number of recently approved drugs which result in impressive yet limited effects. Since SMN has already been enhanced in treated patients, complementary SMN-independent approaches are needed. Previously, a number of altered signaling pathways which regulate motoneuron degeneration have been identified as candidate targets. However, signaling pathways form networks, and their connectivity is still unknown in SMA. Here, we used presymptomatic SMA mice to elucidate the network of altered signaling in SMA. The SMA network is structured in two clusters with AKT and 14-3-3 ζ/δ in their centers. Both clusters are connected by B-Raf as a major signaling hub. The direct interaction of B-Raf with 14-3-3 ζ/δ is important for an efficient neurotrophic activation of the MEK/ERK pathway and crucial for motoneuron survival. Further analyses in SMA mice revealed that both proteins were down-regulated in motoneurons and the spinal cord with B-Raf being reduced at presymptomatic stages. Primary fibroblasts and iPSC-derived motoneurons from SMA patients both showed the same pattern of down-regulation. This mechanism is conserved across species since a SMA model showed less expression of the B-Raf homolog Accordingly, motoneuron survival was rescued by a cell autonomous expression in a SMA model resulting in improved motor functions. This rescue was effective even after the onset of motoneuron degeneration and mediated by the MEK/ERK pathway.
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http://dx.doi.org/10.1073/pnas.2007785118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106332PMC
May 2021

Fibroblast Growth Factor Signalling in the Diseased Nervous System.

Mol Neurobiol 2021 Apr 15. Epub 2021 Apr 15.

Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Hannover, Germany.

Fibroblast growth factors (FGFs) act as key signalling molecules in brain development, maintenance, and repair. They influence the intricate relationship between myelinating cells and axons as well as the association of astrocytic and microglial processes with neuronal perikarya and synapses. Advances in molecular genetics and imaging techniques have allowed novel insights into FGF signalling in recent years. Conditional mouse mutants have revealed the functional significance of neuronal and glial FGF receptors, not only in tissue protection, axon regeneration, and glial proliferation but also in instant behavioural changes. This review provides a summary of recent findings regarding the role of FGFs and their receptors in the nervous system and in the pathogenesis of major neurological and psychiatric disorders.
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http://dx.doi.org/10.1007/s12035-021-02367-0DOI Listing
April 2021

Microtubule-associated protein 1B dysregulates microtubule dynamics and neuronal mitochondrial transport in spinal muscular atrophy.

Hum Mol Genet 2021 02;29(24):3935-3944

Department of Medical Biology, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey.

Spinal muscular atrophy (SMA) is a devastating childhood disease primarily affecting lower motoneurons in the spinal cord. SMA is caused by the loss of functional survival of motoneuron (SMN) protein, leading to structural and functional alterations of the cytoskeleton in motoneurons and other cells. Loss of SMN results in impairments of microtubule architecture, but the underlying mechanisms are not completely understood. In this study, we mechanistically analyzed the effects of SMN deficiency on microtubules, demonstrating a reduced stability together with a reduction in alpha tubulin detyrosination. This was caused by increased levels of microtubule-associated protein 1B and tubulin tyrosine ligase, resulting in mitochondrial mislocalization in SMA. Our findings suggest that altered tubulin post-translational modifications and microtubule-associated proteins are involved in the pathomechanisms of SMA, such as an impaired axonal transport of mitochondria.
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http://dx.doi.org/10.1093/hmg/ddaa275DOI Listing
February 2021

A Single Amino Acid Residue Regulates PTEN-Binding and Stability of the Spinal Muscular Atrophy Protein SMN.

Cells 2020 11 3;9(11). Epub 2020 Nov 3.

Institute of Neuroanatomy and Cell Biology, Hannover Medical School, 30625 Hannover, Germany.

Spinal Muscular Atrophy (SMA) is a neuromuscular disease caused by decreased levels of the survival of motoneuron (SMN) protein. Post-translational mechanisms for regulation of its stability are still elusive. Thus, we aimed to identify regulatory phosphorylation sites that modulate function and stability. Our results show that SMN residues S290 and S292 are phosphorylated, of which SMN pS290 has a detrimental effect on protein stability and nuclear localization. Furthermore, we propose that phosphatase and tensin homolog (PTEN), a novel phosphatase for SMN, counteracts this effect. In light of recent advancements in SMA therapies, a significant need for additional approaches has become apparent. Our study demonstrates S290 as a novel molecular target site to increase the stability of SMN. Characterization of relevant kinases and phosphatases provides not only a new understanding of SMN function, but also constitutes a novel strategy for combinatorial therapeutic approaches to increase the level of SMN in SMA.
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http://dx.doi.org/10.3390/cells9112405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692393PMC
November 2020

The Proteome and Secretome of Cortical Brain Cells Infected With Herpes Simplex Virus.

Front Neurol 2020 27;11:844. Epub 2020 Aug 27.

Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Hanover, Germany.

Infections of the brain with herpes simplex virus type 1 (HSV-1) cause life-threatening Herpes simplex encephalitis (HSE) characterized by viral replication in neurons and neuro-inflammation including an infiltration of peripheral immune cells. HSV-1 reprograms host cells to foster its own replication and for immune evasion, but eventually the immune responses clear the infection in most patients. However, many survivors suffer from long-term neuronal damage and cannot regenerate all brain functions. HSV-1 influences the physiology of neurons, astrocytes, oligodendrocytes and microglia, and significantly changes their protein expression and secretion pattern. To characterize temporal changes upon HSV-1 infection in detail, we inoculated mixed primary cultures of the murine brain cortex, and performed quantitative mass spectrometry analyses of the cell-associated proteome and the secretome. We identified 28 differentially regulated host proteins influencing inflammasome formation and intracellular vesicle trafficking during endocytosis and secretion. The NIMA-related kinase 7 (NEK7), a critical component of the inflammasome, and ArfGap1, a regulator of endocytosis, were significantly up-regulated upon HSV-1 infection. In the secretome, we identified 71 proteins including guidance cues regulating axonal regeneration, such as semaphorin6D, which were enriched in the conditioned media of HSV-1 infected cells. Modulation of inflammasome activity and intracellular membrane traffic are critical for HSV-1 cell entry, virus assembly, and intracellular spread. Our proteome analysis provides first clues on host factors that might dampen the inflammasome response and modulate intracellular vesicle transport to promote HSV infection of the brain. Furthermore, our secretome analysis revealed a set of proteins involved in neuroregeneration that might foster neuronal repair processes to restore brain functions after clearance of an HSV-1 infection.
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http://dx.doi.org/10.3389/fneur.2020.00844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481480PMC
August 2020

Altered bone development with impaired cartilage formation precedes neuromuscular symptoms in spinal muscular atrophy.

Hum Mol Genet 2020 09;29(16):2662-2673

Pediatric Orthopedics, Department of Trauma, Orthopedic and Plastic Surgery, University Medical Center Goettingen, Goettingen, Germany.

Spinal muscular atrophy (SMA) is a fatal neurodegenerative disease of newborns and children caused by mutations or deletions of the survival of motoneuron gene 1 resulting in low levels of the SMN protein. While neuromuscular degeneration is the cardinal symptom of the disease, the reduction of the ubiquitously expressed SMN additionally elicits non-motoneuron symptoms. Impaired bone development is a key feature of SMA, but it is yet unknown whether this is an indirect functional consequence of muscle weakness or caused by bone-intrinsic mechanisms. Therefore, we radiologically examined SMA patients in a prospective, non-randomized cohort study characterizing bone size and bone mineral density (BMD) and performed equivalent measurements in pre-symptomatic SMA mice. BMD as well as lumbar vertebral body size were significantly reduced in SMA patients. This growth defect but not BMD reduction was confirmed in SMA mice by μCT before the onset of neuromuscular symptoms indicating that it is at least partially independent of neuromuscular degeneration. Interestingly, the number of chondroblasts in the hypertrophic zone of the growth plate was significantly reduced. This was underlined by RNAseq and expression data from developing SMA mice vertebral bodies, which revealed molecular changes related to cell division and cartilage remodeling. Together, these findings suggest a bone intrinsic defect in SMA. This phenotype may not be rescued by novel drugs that enhance SMN levels in the central nervous system only.
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http://dx.doi.org/10.1093/hmg/ddaa145DOI Listing
September 2020

Renal pathology in a mouse model of severe Spinal Muscular Atrophy is associated with downregulation of Glial Cell-Line Derived Neurotrophic Factor (GDNF).

Hum Mol Genet 2020 08;29(14):2365-2378

Institute of Medical Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK.

Spinal muscular atrophy (SMA) occurs as a result of cell-ubiquitous depletion of the essential survival motor neuron (SMN) protein. Characteristic disease pathology is driven by a particular vulnerability of the ventral motor neurons of the spinal cord to decreased SMN. Perhaps not surprisingly, many other organ systems are also impacted by SMN depletion. The normal kidney expresses very high levels of SMN protein, equivalent to those found in the nervous system and liver, and levels are dramatically lowered by ~90-95% in mouse models of SMA. Taken together, these data suggest that renal pathology may be present in SMA. We have addressed this using an established mouse model of severe SMA. Nephron number, as assessed by gold standard stereological techniques, was significantly reduced. In addition, morphological assessment showed decreased renal vasculature, particularly of the glomerular capillary knot, dysregulation of nephrin and collagen IV, and ultrastructural changes in the trilaminar filtration layers of the nephron. To explore the molecular drivers underpinning this process, we correlated these findings with quantitative PCR measurements and protein analyses of glial cell-line-derived neurotrophic factor, a crucial factor in ureteric bud branching and subsequent nephron development. Glial cell-line-derived neurotrophic factor levels were significantly reduced at early stages of disease in SMA mice. Collectively, these findings reveal significant renal pathology in a mouse model of severe SMA, further reinforcing the need to develop and administer systemic therapies for this neuromuscular disease.
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http://dx.doi.org/10.1093/hmg/ddaa126DOI Listing
August 2020

Light-powered CO fixation in a chloroplast mimic with natural and synthetic parts.

Science 2020 05;368(6491):649-654

Department of Biochemistry and Synthetic Metabolism, Max Planck Institute for Terrestrial Microbiology, D-35043 Marburg, Germany.

Nature integrates complex biosynthetic and energy-converting tasks within compartments such as chloroplasts and mitochondria. Chloroplasts convert light into chemical energy, driving carbon dioxide fixation. We used microfluidics to develop a chloroplast mimic by encapsulating and operating photosynthetic membranes in cell-sized droplets. These droplets can be energized by light to power enzymes or enzyme cascades and analyzed for their catalytic properties in multiplex and real time. We demonstrate how these microdroplets can be programmed and controlled by adjusting internal compositions and by using light as an external trigger. We showcase the capability of our platform by integrating the crotonyl-coenzyme A (CoA)/ethylmalonyl-CoA/hydroxybutyryl-CoA (CETCH) cycle, a synthetic network for carbon dioxide conversion, to create an artificial photosynthetic system that interfaces the natural and the synthetic biological worlds.
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http://dx.doi.org/10.1126/science.aaz6802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610767PMC
May 2020

Muscle overexpression of Klf15 via an AAV8-Spc5-12 construct does not provide benefits in spinal muscular atrophy mice.

Gene Ther 2019 11 20;27(10-11):505-515. Epub 2020 Apr 20.

Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by loss of the survival motor neuron (SMN) gene. While there are currently two approved gene-based therapies for SMA, availability, high cost, and differences in patient response indicate that alternative treatment options are needed. Optimal therapeutic strategies will likely be a combination of SMN-dependent and -independent treatments aimed at alleviating symptoms in the central nervous system and peripheral muscles. Krüppel-like factor 15 (KLF15) is a transcription factor that regulates key metabolic and ergogenic pathways in muscle. We have recently reported significant downregulation of Klf15 in muscle of presymptomatic SMA mice. Importantly, perinatal upregulation of Klf15 via transgenic and pharmacological methods resulted in improved disease phenotypes in SMA mice, including weight and survival. In the current study, we designed an adeno-associated virus serotype 8 (AAV8) vector to overexpress a codon-optimized Klf15 cDNA under the muscle-specific Spc5-12 promoter (AAV8-Klf15). Administration of AAV8-Klf15 to severe Taiwanese Smn;SMN2 or intermediate Smn SMA mice significantly increased Klf15 expression in muscle. We also observed significant activity of the AAV8-Klf15 vector in liver and heart. AAV8-mediated Klf15 overexpression moderately improved survival in the Smn model but not in the Taiwanese mice. An inability to specifically induce Klf15 expression at physiological levels in a time- and tissue-dependent manner may have contributed to this limited efficacy. Thus, our work demonstrates that an AAV8-Spc5-12 vector induces high gene expression as early as P2 in several tissues including muscle, heart, and liver, but highlights the challenges of achieving meaningful vector-mediated transgene expression of Klf15.
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http://dx.doi.org/10.1038/s41434-020-0146-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674152PMC
November 2019

The Need for SMN-Independent Treatments of Spinal Muscular Atrophy (SMA) to Complement SMN-Enhancing Drugs.

Front Neurol 2020 3;11:45. Epub 2020 Feb 3.

Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Hannover, Germany.

Spinal Muscular Atrophy (SMA) is monogenic motoneuron disease caused by low levels of the Survival of Motoneuron protein (SMN). Recently, two different drugs were approved for the treatment of the disease. The antisense oligonucleotide Nusinersen/Spinraza® and the gene replacement therapy Onasemnogene Abeparvovec/Zolgensma® both enhance SMN levels. These treatments result in impressive benefits for the patients. However, there is a significant number of non-responders and an intervention delay has a strong negative impact on the efficacy. Obviously, later stages of motoneuron degeneration cannot be reversed by SMN-restoration. Therefore, complementary, SMN-independent strategies are needed which are able to address such SMN-irreversible degenerative processes. Those are defined as pathological alterations which are not reversed by SMN-restoration for a given dose and intervention delay. It is crucial to tailor SMN-independent approaches to the novel clinical situation with SMN-restoring treatments. On the molecular level, such SMN-irreversible changes become manifest in altered signaling modules as described by molecular systems biology. Based on our current knowledge about altered signaling, we introduce a network approach for an informed decision for the most potent SMN-independent treatment targets. Finally, we present recommendations for the identification of novel treatments which can be combined with SMN-restoring drugs.
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http://dx.doi.org/10.3389/fneur.2020.00045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7009174PMC
February 2020

Profilin2a-phosphorylation as a regulatory mechanism for actin dynamics.

FASEB J 2020 02 12;34(2):2147-2160. Epub 2019 Dec 12.

Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Hannover, Germany.

Profilin is a major regulator of actin dynamics in multiple specific processes localized in different cellular compartments. This specificity is not only meditated by its binding to actin but also its interaction with phospholipids such as phosphatidylinositol (4,5)-bisphosphate (PIP ) at the membrane and a plethora of proteins containing poly-L-proline (PLP) stretches. These interactions are fine-tuned by posttranslational modifications such as phosphorylation. Several phospho-sites have already been identified for profilin1, the ubiquitously expressed isoform. However, little is known about the phosphorylation of profilin2a. Profilin2a is a neuronal isoform important for synapse function. Here, we identified several putative profilin2a phospho-sites in silico and tested recombinant phospho-mimetics with regard to their actin-, PLP-, and PIP -binding properties. Moreover, we assessed their impact on actin dynamics employing a pyrene-actin polymerization assay. Results indicate that distinct phospho-sites modulate specific profilin2a functions. We could identify a molecular switch site at serine residue 71 which completely abrogated actin binding-as well as other sites important for fine-tuning of different functions, for example, tyrosine 29 for PLP binding. Our findings suggest that differential profilin2a phosphorylation is a sensitive mechanism for regulating its neuronal functions. Moreover, the dysregulation of profilin2a phosphorylation may contribute to neurodegeneration.
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http://dx.doi.org/10.1096/fj.201901883RDOI Listing
February 2020

Resolution of pathogenic R-loops rescues motor neuron degeneration in spinal muscular atrophy.

Brain 2020 01;143(1):2-5

Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Hannover, Germany.

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http://dx.doi.org/10.1093/brain/awz394DOI Listing
January 2020

HSV-1 triggers paracrine fibroblast growth factor response from cortical brain cells via immediate-early protein ICP0.

J Neuroinflammation 2019 Dec 2;16(1):248. Epub 2019 Dec 2.

Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Hannover, Germany.

Background: Herpes simplex virus-1 (HSV-1) infections of the central nervous system (CNS) can result in HSV-1 encephalitis (HSE) which is characterized by severe brain damage and long-term disabilities. Different cell types including neurons and astrocytes become infected in the course of an HSE which leads to an activation of glial cells. Activated glial cells change their neurotrophic factor profile and modulate inflammation and repair. The superfamily of fibroblast growth factors (FGFs) is one of the largest family of neurotrophic factors comprising 22 ligands. FGFs induce pro-survival signaling in neurons and an anti-inflammatory answer in glial cells thereby providing a coordinated tissue response which favors repair over inflammation. Here, we hypothesize that FGF expression is altered in HSV-1-infected CNS cells.

Method: We employed primary murine cortical cultures comprising a mixed cell population of astrocytes, neurons, microglia, and oligodendrocytes. Astrocyte reactivity was morphometrically monitored by an automated image analysis algorithm as well as by analyses of A1/A2 marker expression. Altered FGF expression was detected by quantitative real-time PCR and its paracrine FGF activity. In addition, HSV-1 mutants were employed to characterize viral factors important for FGF responses of infected host cells.

Results: Astrocytes in HSV-1-infected cortical cultures were transiently activated and became hypertrophic and expressed both A1- and A2-markers. Consistently, a number of FGFs were transiently upregulated inducing paracrine neurotrophic signaling in neighboring cells. Most prominently, FGF-4, FGF-8, FGF-9, and FGF-15 became upregulated in a switch-on like mechanism. This effect was specific for CNS cells and for a fully functional HSV-1. Moreover, the viral protein ICP0 critically mediated the FGF switch-on mechanism.

Conclusions: HSV-1 uses the viral protein ICP0 for the induction of FGF-expression in CNS cells. Thus, we propose that HSV-1 triggers FGF activity in the CNS for a modulation of tissue response upon infection.
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http://dx.doi.org/10.1186/s12974-019-1647-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889453PMC
December 2019

Marine Proteobacteria metabolize glycolate via the β-hydroxyaspartate cycle.

Nature 2019 11 13;575(7783):500-504. Epub 2019 Nov 13.

Department of Biochemistry & Synthetic Metabolism, Max Planck Institute for Terrestrial Microbiology, Marburg, Germany.

One of the most abundant sources of organic carbon in the ocean is glycolate, the secretion of which by marine phytoplankton results in an estimated annual flux of one petagram of glycolate in marine environments. Although it is generally accepted that glycolate is oxidized to glyoxylate by marine bacteria, the further fate of this C metabolite is not well understood. Here we show that ubiquitous marine Proteobacteria are able to assimilate glyoxylate via the β-hydroxyaspartate cycle (BHAC) that was originally proposed 56 years ago. We elucidate the biochemistry of the BHAC and describe the structure of its key enzymes, including a previously unknown primary imine reductase. Overall, the BHAC enables the direct production of oxaloacetate from glyoxylate through only four enzymatic steps, representing-to our knowledge-the most efficient glyoxylate assimilation route described to date. Analysis of marine metagenomes shows that the BHAC is globally distributed and on average 20-fold more abundant than the glycerate pathway, the only other known pathway for net glyoxylate assimilation. In a field study of a phytoplankton bloom, we show that glycolate is present in high nanomolar concentrations and taken up by prokaryotes at rates that allow a full turnover of the glycolate pool within one week. During the bloom, genes that encode BHAC key enzymes are present in up to 1.5% of the bacterial community and actively transcribed, supporting the role of the BHAC in glycolate assimilation and suggesting a previously undescribed trophic interaction between autotrophic phytoplankton and heterotrophic bacterioplankton.
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http://dx.doi.org/10.1038/s41586-019-1748-4DOI Listing
November 2019

FOCAD loss impacts microtubule assembly, G2/M progression and patient survival in astrocytic gliomas.

Acta Neuropathol 2020 01 31;139(1):175-192. Epub 2019 Aug 31.

Department of Human Genetics OE 6300, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.

In search of novel genes associated with glioma pathogenesis, we have previously shown frequent deletions of the KIAA1797/FOCAD gene in malignant gliomas, and a tumor suppressor function of the encoded focadhesin impacting proliferation and migration of glioma cells in vitro and in vivo. Here, we examined an association of reduced FOCAD gene copy number with overall survival of patients with astrocytic gliomas, and addressed the molecular mechanisms that govern the suppressive effect of focadhesin on glioma growth. FOCAD loss was associated with inferior outcome in patients with isocitrate dehydrogenase 1 or 2 (IDH)-mutant astrocytic gliomas of WHO grades II-IV. Multivariate analysis considering age at diagnosis as well as IDH mutation, MGMT promoter methylation, and CDKN2A/B homozygous deletion status confirmed reduced FOCAD gene copy number as a prognostic factor for overall survival. Using a yeast two-hybrid screen and pull-down assays, tubulin beta-6 and other tubulin family members were identified as novel focadhesin-interacting partners. Tubulins and focadhesin co-localized to centrosomes where focadhesin was enriched in proximity to centrioles. Focadhesin was recruited to microtubules via its interaction partner SLAIN motif family member 2 and reduced microtubule assembly rates, possibly explaining the focadhesin-dependent decrease in cell migration. During the cell cycle, focadhesin levels peaked in G2/M phase and influenced time-dependent G2/M progression potentially via polo like kinase 1 phosphorylation, providing a possible explanation for focadhesin-dependent cell growth reduction. We conclude that FOCAD loss may promote biological aggressiveness and worsen clinical outcome of diffuse astrocytic gliomas by enhancing microtubule assembly and accelerating G2/M phase progression.
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http://dx.doi.org/10.1007/s00401-019-02067-zDOI Listing
January 2020

Abnormal fatty acid metabolism is a core component of spinal muscular atrophy.

Ann Clin Transl Neurol 2019 08 26;6(8):1519-1532. Epub 2019 Jul 26.

Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Objective: Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder leading to paralysis and subsequent death in young children. Initially considered a motor neuron disease, extra-neuronal involvement is increasingly recognized. The primary goal of this study was to investigate alterations in lipid metabolism in SMA patients and mouse models of the disease.

Methods: We analyzed clinical data collected from a large cohort of pediatric SMA type I-III patients as well as SMA type I liver necropsy data. In parallel, we performed histology, lipid analysis, and transcript profiling in mouse models of SMA.

Results: We identify an increased susceptibility to developing dyslipidemia in a cohort of 72 SMA patients and liver steatosis in pathological samples. Similarly, fatty acid metabolic abnormalities were present in all SMA mouse models studied. Specifically, Smn mice displayed elevated hepatic triglycerides and dyslipidemia, resembling non-alcoholic fatty liver disease (NAFLD). Interestingly, this phenotype appeared prior to denervation.

Interpretation: This work highlights metabolic abnormalities as an important feature of SMA, suggesting implementation of nutritional and screening guidelines in patients, as such defects are likely to increase metabolic distress and cardiovascular risk. This study emphasizes the need for a systemic therapeutic approach to ensure maximal benefits for all SMA patients throughout their life.
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http://dx.doi.org/10.1002/acn3.50855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689695PMC
August 2019

Vitamin D improves endothelial barrier integrity and counteracts inflammatory effects on endothelial progenitor cells.

FASEB J 2019 08 14;33(8):9142-9153. Epub 2019 May 14.

Gynecology Research Unit, Hannover Medical School, Hannover, Germany.

Endothelial colony-forming cells (ECFCs), a proliferative subpopulation of endothelial progenitor cells, are involved in angiogenesis and endothelial repair. In this study, we investigated endothelial barrier characteristics of ECFCs, whether vitamin D supports cell-cell adhesion and barrier integrity, and how it affects ECFC mobilization and actin dynamics. Although ECFC barrier was disrupted under inflammatory conditions, this effect was rescued by vitamin D treatment, leading to higher stability of an ECFC monolayer. Furthermore, vitamin D enhanced ECFC mobilization toward directional migration. In addition, immunocytochemistry, quantitative real-time PCR, and immunoblotting analysis showed that vitamin D increased endothelial interconnections through vascular endothelial cadherin (VE-cadherin) junctions and by impacting cell dynamics through cofilin and VE-cadherin phosphorylation. Our results suggest that vitamin D treatment efficiently counteracts inflammation in an ECFC monolayer, resulting in higher ECFC barrier integrity. This study provides evidence of a new beneficial effect of vitamin D for ECFC homeostasis.-Schröder-Heurich, B., von Hardenberg, S., Brodowski, L., Kipke, B., Meyer, N., Borns, K., von Kaisenberg, C. S., Brinkmann, H., Claus, P., von Versen-Höynck, F. Vitamin D improves endothelial barrier integrity and counteracts inflammatory effects on endothelial progenitor cells.
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http://dx.doi.org/10.1096/fj.201802750RRDOI Listing
August 2019

Structure, function and resilience to desiccation of methanogenic microbial communities in temporarily inundated soils of the Amazon rainforest (Cunia Reserve, Rondonia).

Environ Microbiol 2019 05 19;21(5):1702-1717. Epub 2019 Mar 19.

Max Planck Institute for Terrestrial Microbiology, Karl-von-Frisch-Str. 10, 35043, Marburg, Germany.

The floodplain of the Amazon River is a large source for the greenhouse gas methane, but the soil microbial communities and processes involved are little known. We studied the structure and function of the methanogenic microbial communities in soils across different inundation regimes in the Cunia Reserve, encompassing nonflooded forest soil (dry forest), occasionally flooded Igapo soils (dry Igapo), long time flooded Igapo soils (wet Igapo) and sediments from Igarape streams (Igarape). We also investigated a Transect (four sites) from the water shoreline into the dry forest. The potential and resilience of the CH production process were studied in the original soil samples upon anaerobic incubation and again after artificial desiccation and rewetting. Bacterial and archaeal 16S rRNA genes and methanogenic mcrA were always present in the soils, except in dry forest soils where mcrA increased only upon anaerobic incubation. NMDS analysis showed a clear effect of desiccation and rewetting treatments on both bacterial and archaeal communities. However, the effects of the different sites were less pronounced, with the exception of Igarape. After anaerobic incubation, methanogenic taxa became more abundant among the Archaea, while there was only little change among the Bacteria. Contribution of hydrogenotrophic methanogenesis was usually around 40%. After desiccation and rewetting, we found that Firmicutes, Methanocellales and Methanosarcinaceae became the dominant taxa, but rates and pathways of CH production stayed similar. Such change was also observed in soils from the Transects. The results indicate that microbial community structures of Amazonian soils will in general be strongly affected by flooding and drainage events, while differences between specific field sites will be comparatively minor.
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http://dx.doi.org/10.1111/1462-2920.14535DOI Listing
May 2019

Gene expression profiles in neurological tissues during West Nile virus infection: a critical meta-analysis.

BMC Genomics 2018 Jul 13;19(1):530. Epub 2018 Jul 13.

Institute for Animal Breeding and Genetics, University of Veterinary Medicine Hannover, Foundation, Bünteweg 17p, Hanover, 30559, Germany.

Background: Infections with the West Nile virus (WNV) can attack neurological tissues in the host and alter gene expression levels therein. Several individual studies have analyzed these changes in the transcriptome based on measurements with DNA microarrays. Individual microarray studies produce a high-dimensional data structure with the number of studied genes exceeding the available sample size by far. Therefore, the level of scientific evidence of these studies is rather low and results can remain uncertain. Furthermore, the individual studies concentrate on different types of tissues or different time points after infection. A general statement regarding the transcriptional changes through WNV infection in neurological tissues is therefore hard to make. We screened public databases for transcriptome expression studies related to WNV infections and used different analysis pipelines to perform meta-analyses of these data with the goal of obtaining more stable results and increasing the level of evidence.

Results: We generated new lists of genes differentially expressed between WNV infected neurological tissues and control samples. A comparison with these genes to findings of a meta-analysis of immunological tissues is performed to figure out tissue-specific differences. While 5.879 genes were identified exclusively in the neurological tissues, 15 genes were found exclusively in the immunological tissues, and 44 genes were commonly detected in both tissues. Most findings of the original studies could be confirmed by the meta-analysis with a higher statistical power, but some genes and GO terms related to WNV were newly detected, too. In addition, we identified gene ontology terms related to certain infection processes, which are significantly enriched among the differentially expressed genes. In the neurological tissues, 17 gene ontology terms were found significantly different, and 2 terms in the immunological tissues.

Conclusions: A critical discussion of our findings shows benefits but also limitations of the meta-analytic approach. In summary, the produced gene lists, identified gene ontology terms and network reconstructions appear to be more reliable than the results from the individual studies. Our meta-analysis provides a basis for further research on the transcriptional mechanisms by WNV infections in neurological tissues.
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http://dx.doi.org/10.1186/s12864-018-4914-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6044103PMC
July 2018

Light modulation ameliorates expression of circadian genes and disease progression in spinal muscular atrophy mice.

Hum Mol Genet 2018 10;27(20):3582-3597

Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.

Physiology and behaviour are critically dependent on circadian regulation via a core set of clock genes, dysregulation of which leads to metabolic and sleep disturbances. Metabolic and sleep perturbations occur in spinal muscular atrophy (SMA), a neuromuscular disorder caused by loss of the survival motor neuron (SMN) protein and characterized by motor neuron loss and muscle atrophy. We therefore investigated the expression of circadian rhythm genes in various metabolic tissues and spinal cord of the Taiwanese Smn-/-;SMN2 SMA animal model. We demonstrate a dysregulated expression of the core clock genes (clock, ARNTL/Bmal1, Cry1/2, Per1/2) and clock output genes (Nr1d1 and Dbp) in SMA tissues during disease progression. We also uncover an age- and tissue-dependent diurnal expression of the Smn gene. Importantly, we observe molecular and phenotypic corrections in SMA mice following direct light modulation. Our study identifies a key relationship between an SMA pathology and peripheral core clock gene dysregulation, highlights the influence of SMN on peripheral circadian regulation and metabolism and has significant implications for the development of peripheral therapeutic approaches and clinical care management of SMA patients.
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http://dx.doi.org/10.1093/hmg/ddy249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168969PMC
October 2018

Nanodiamonds as "artificial proteins": Regulation of a cell signalling system using low nanomolar solutions of inorganic nanocrystals.

Biomaterials 2018 09 21;176:106-121. Epub 2018 May 21.

Department of Biology, Faculty of Medicine, Masaryk University, 62500, Brno, Czech Republic; Institute of Animal Physiology and Genetics of the CAS, 60200, Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, 65691, Brno, Czech Republic. Electronic address:

The blocking of specific protein-protein interactions using nanoparticles is an emerging alternative to small molecule-based therapeutic interventions. However, the nanoparticles designed as "artificial proteins" generally require modification of their surface with (bio)organic molecules and/or polymers to ensure their selectivity and specificity of action. Here, we show that nanosized diamond crystals (nanodiamonds, NDs) without any synthetically installed (bio)organic interface enable the specific and efficient targeting of the family of extracellular signalling molecules known as fibroblast growth factors (FGFs). We found that low nanomolar solutions of detonation NDs with positive ζ-potential strongly associate with multiple FGF ligands present at sub-nanomolar concentrations and effectively neutralize the effects of FGF signalling in cells without interfering with other growth factor systems and serum proteins unrelated to FGFs. We identified an evolutionarily conserved FGF recognition motif, ∼17 amino acids long, that contributes to the selectivity of the ND-FGF interaction. In addition, we inserted this motif into a de novo constructed chimeric protein, which significantly improved its interaction with NDs. We demonstrated that the interaction of NDs, as purely inorganic nanoparticles, with proteins can mitigate pathological FGF signalling and promote the restoration of cartilage growth in a mouse limb explant model. Based on our observations, we foresee that NDs may potentially be applied as nanotherapeutics to neutralize disease-related activities of FGFs in vivo.
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http://dx.doi.org/10.1016/j.biomaterials.2018.05.030DOI Listing
September 2018

Interventions Targeting Glucocorticoid-Krüppel-like Factor 15-Branched-Chain Amino Acid Signaling Improve Disease Phenotypes in Spinal Muscular Atrophy Mice.

EBioMedicine 2018 May 4;31:226-242. Epub 2018 May 4.

Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom. Electronic address:

The circadian glucocorticoid-Krüppel-like factor 15-branched-chain amino acid (GC-KLF15-BCAA) signaling pathway is a key regulatory axis in muscle, whose imbalance has wide-reaching effects on metabolic homeostasis. Spinal muscular atrophy (SMA) is a neuromuscular disorder also characterized by intrinsic muscle pathologies, metabolic abnormalities and disrupted sleep patterns, which can influence or be influenced by circadian regulatory networks that control behavioral and metabolic rhythms. We therefore set out to investigate the contribution of the GC-KLF15-BCAA pathway in SMA pathophysiology of Taiwanese Smn;SMN2 and Smn mouse models. We thus uncover substantial dysregulation of GC-KLF15-BCAA diurnal rhythmicity in serum, skeletal muscle and metabolic tissues of SMA mice. Importantly, modulating the components of the GC-KLF15-BCAA pathway via pharmacological (prednisolone), genetic (muscle-specific Klf15 overexpression) and dietary (BCAA supplementation) interventions significantly improves disease phenotypes in SMA mice. Our study highlights the GC-KLF15-BCAA pathway as a contributor to SMA pathogenesis and provides several treatment avenues to alleviate peripheral manifestations of the disease. The therapeutic potential of targeting metabolic perturbations by diet and commercially available drugs could have a broader implementation across other neuromuscular and metabolic disorders characterized by altered GC-KLF15-BCAA signaling.
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http://dx.doi.org/10.1016/j.ebiom.2018.04.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013932PMC
May 2018

Intact interleukin-10 receptor signaling protects from hippocampal damage elicited by experimental neurotropic virus infection of SJL mice.

Sci Rep 2018 04 17;8(1):6106. Epub 2018 Apr 17.

Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany.

Theiler's murine encephalomyelitis virus (TMEV) infection represents an experimental mouse model to study hippocampal damage induced by neurotropic viruses. IL-10 is a pleiotropic cytokine with profound anti-inflammatory properties, which critically controls immune homeostasis. In order to analyze IL-10R signaling following virus-induced polioencephalitis, SJL mice were intracerebrally infected with TMEV. RNA-based next generation sequencing revealed an up-regulation of Il10, Il10rα and further genes involved in IL-10 downstream signaling, including Jak1, Socs3 and Stat3 in the brain upon infection. Subsequent antibody-mediated blockade of IL-10R signaling led to enhanced hippocampal damage with neuronal loss and increased recruitment of CD3 T cells, CD45R B cells and an up-regulation of Il1α mRNA. Increased expression of Tgfβ and Foxp3 as well as accumulation of Foxp3 regulatory T cells and arginase-1 macrophages/microglia was detected in the hippocampus, representing a potential compensatory mechanism following disturbed IL-10R signaling. Additionally, an increased peripheral Chi3l3 expression was found in spleens of infected mice, which may embody reactive regulatory mechanisms for prevention of excessive immunopathology. The present study highlights the importance of IL-10R signaling for immune regulation and its neuroprotective properties in the context of an acute neurotropic virus infection.
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http://dx.doi.org/10.1038/s41598-018-24378-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5904160PMC
April 2018

Metalloprotease-mediated cleavage of PlexinD1 and its sequestration to actin rods in the motoneuron disease spinal muscular atrophy (SMA).

Hum Mol Genet 2017 10;26(20):3946-3959

Institute of Neuroanatomy and Cell Biology, Hannover Medical School, 30625 Hannover, Germany.

Cytoskeletal rearrangement during axon growth is mediated by guidance receptors and their ligands which act either as repellent, attractant or both. Regulation of the actin cytoskeleton is disturbed in Spinal Muscular Atrophy (SMA), a devastating neurodegenerative disease affecting mainly motoneurons, but receptor-ligand interactions leading to the dysregulation causing SMA are poorly understood. In this study, we analysed the role of the guidance receptor PlexinD1 in SMA pathogenesis. We showed that PlexinD1 is cleaved by metalloproteases in SMA and that this cleavage switches its function from an attractant to repellent. Moreover, we found that the PlexinD1 cleavage product binds to actin rods, pathological aggregate-like structures which had so far been described for age-related neurodegenerative diseases. Our data suggest a novel disease mechanism for SMA involving formation of actin rods as a molecular sink for a cleaved PlexinD1 fragment leading to dysregulation of receptor signaling.
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http://dx.doi.org/10.1093/hmg/ddx282DOI Listing
October 2017

ERK and ROCK functionally interact in a signaling network that is compensationally upregulated in Spinal Muscular Atrophy.

Neurobiol Dis 2017 Dec 12;108:352-361. Epub 2017 Sep 12.

Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Hannover, Germany; Center for Systems Neuroscience (ZSN), Hannover, Germany. Electronic address:

Spinal Muscular Atrophy (SMA) is a motoneuron disease caused by low levels of functional survival of motoneuron protein (SMN). Molecular disease mechanisms downstream of functional SMN loss are still largely unknown. Previous studies suggested an involvement of Rho kinase (ROCK) as well as the extracellular signal-regulated kinases (ERK) pathways in the pathomechanism. Both pathways are bi-directionally linked and inhibit each other. Thus, we hypothesize that both pathways regulate SMA pathophysiology in vivo in a combined manner rather than acting separately. Here, we applied the repurposed drugs, selumetinib, an ERK inhibitor, and the ROCK inhibitor fasudil to severe SMA mice. Thereby, separately applied inhibitors as well as a combination enabled us to explore the impact of the ROCK-ERK signaling network on SMA pathophysiology. ROCK inhibition specifically ameliorated the phenotype of selumetinib-treated SMA mice demonstrating an efficient ROCK to ERK crosstalk relevant for the SMA pathophysiology. However, ERK inhibition alone aggravated the condition of SMA mice and reduced the number of motoneurons indicating a compensatory hyper-activation of ERK in motoneurons. Taken together, we identified a regulatory network acting downstream of SMN depletion and upstream of the SMA pathophysiology thus being a future treatment target in combination with SMN dependent strategies.
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http://dx.doi.org/10.1016/j.nbd.2017.09.005DOI Listing
December 2017

The Actin Cytoskeleton in SMA and ALS: How Does It Contribute to Motoneuron Degeneration?

Neuroscientist 2018 02 1;24(1):54-72. Epub 2017 May 1.

1 Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Hannover, Germany.

Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are neurodegenerative diseases with overlapping clinical phenotypes based on impaired motoneuron function. However, the pathomechanisms of both diseases are largely unknown, and it is still unclear whether they converge on the molecular level. SMA is a monogenic disease caused by low levels of functional Survival of Motoneuron (SMN) protein, whereas ALS involves multiple genes as well as environmental factors. Recent evidence argues for involvement of actin regulation as a causative and dysregulated process in both diseases. ALS-causing mutations in the actin-binding protein profilin-1 as well as the ability of the SMN protein to directly bind to profilins argue in favor of a common molecular mechanism involving the actin cytoskeleton. Profilins are major regulat ors of actin-dynamics being involved in multiple neuronal motility and transport processes as well as modulation of synaptic functions that are impaired in models of both motoneuron diseases. In this article, we review the current literature in SMA and ALS research with a focus on the actin cytoskeleton. We propose a common molecular mechanism that explains the degeneration of motoneurons for SMA and some cases of ALS.
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http://dx.doi.org/10.1177/1073858417705059DOI Listing
February 2018

Neuronal Dysfunction in iPSC-Derived Medium Spiny Neurons from Chorea-Acanthocytosis Patients Is Reversed by Src Kinase Inhibition and F-Actin Stabilization.

J Neurosci 2016 11;36(47):12027-12043

Department of Neurology and

Chorea-acanthocytosis (ChAc) is a fatal neurological disorder characterized by red blood cell acanthocytes and striatal neurodegeneration. Recently, severe cell membrane disturbances based on depolymerized cortical actin and an elevated Lyn kinase activity in erythrocytes from ChAc patients were identified. How this contributes to the mechanism of neurodegeneration is still unknown. To gain insight into the pathophysiology, we established a ChAc patient-derived induced pluripotent stem cell model and an efficient differentiation protocol providing a large population of human striatal medium spiny neurons (MSNs), the main target of neurodegeneration in ChAc. Patient-derived MSNs displayed enhanced neurite outgrowth and ramification, whereas synaptic density was similar to controls. Electrophysiological analysis revealed a pathologically elevated synaptic activity in ChAc MSNs. Treatment with the F-actin stabilizer phallacidin or the Src kinase inhibitor PP2 resulted in the significant reduction of disinhibited synaptic currents to healthy control levels, suggesting a Src kinase- and actin-dependent mechanism. This was underlined by increased G/F-actin ratios and elevated Lyn kinase activity in patient-derived MSNs. These data indicate that F-actin stabilization and Src kinase inhibition represent potential therapeutic targets in ChAc that may restore neuronal function.

Significance Statement: Chorea-acanthocytosis (ChAc) is a fatal neurodegenerative disease without a known cure. To gain pathophysiological insight, we newly established a human in vitro model using skin biopsies from ChAc patients to generate disease-specific induced pluripotent stem cells (iPSCs) and developed an efficient iPSC differentiation protocol providing striatal medium spiny neurons. Using patch-clamp electrophysiology, we detected a pathologically enhanced synaptic activity in ChAc neurons. Healthy control levels of synaptic activity could be restored by treatment of ChAc neurons with the F-actin stabilizer phallacidin and the Src kinase inhibitor PP2. Because Src kinases are involved in bridging the membrane to the actin cytoskeleton by membrane protein phosphorylation, our data suggest an actin-dependent mechanism of this dysfunctional phenotype and potential treatment targets in ChAc.
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http://dx.doi.org/10.1523/JNEUROSCI.0456-16.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604921PMC
November 2016

From Barley Straw to Valuable Polyols: A Sustainable Process Using Ethanol/Water Mixtures and Hydrogenolysis over Ruthenium-Tungsten Catalyst.

ChemSusChem 2016 Oct 25;9(19):2804-2815. Epub 2016 Aug 25.

Technical University Darmstadt, Department Chemistry, Chemical Technology II, Ernst-Berl-Institute for Technical and Macromolecular Chemistry, Alarich-Weiss-Strasse 8, 64289, Darmstadt, Germany.

Organosolv fractionation of barley straw followed by a hydrogenolysis reaction of the resulting organosolv pulp over a heterogeneous catalyst containing ruthenium and tungsten on activated carbon (Ru-W/AC) is a potential pathway to produce valuable chemicals from lignocellulose-based feedstock in a future biorefinery. Polyols, such as ethylene glycol, propylene glycol, or 1,2-butanediol, can be obtained with a very high yield of 70 % using organosolv barley pulp pretreated in a 50:50 wt % ethanol/water solution at 200 °C and a processing time of one hour. Moreover, we investigated the influence of several pretreatment parameters (e.g., solvent/water ratio, reaction temperature, and reaction time) on the pulp composition and product distribution obtained during the hydrogenolysis reaction to reduce the production of undesired side molecules. Finally, the optimal organosolv pretreatment conditions for straw were successfully transferred to other lignocellulose-based feedstock, namely bamboo foliage and hemp shives.
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http://dx.doi.org/10.1002/cssc.201600695DOI Listing
October 2016