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91 Publications visible to you, out of a total of 91
MicroRNAs from extracellular vesicles as a signature for Parkinson's disease.

Abstract (Expand)

In the present study, we have demonstrated that extracellular vesicles (EVs) derived from cerebrospinal fluid (CSF) represent a promising source for the identification of a novel miRNA signatures in … Parkinson's disease (PD). Using next‐generation small‐RNA sequencing, we present for the first time the complete and quantitative microRNAome of EVs isolated from human CSF of PD and age‐correlated controls (CTR). In parallel, we performed CSF proteomic profiling of overlapping patient cohorts, which revealed the deregulation of disease‐relevant pathways similar to the ones obtained with the parallel miRNA analyses, supporting the results for the identified signature.

Authors: Lucas Caldi Gomes, Anna-Elisa Roser, Gaurav Jain, Tonatiuh Pena Centeno, Fabian Maass, Lukas Schilde, Caroline May, Anja Schneider, Mathias Bähr, Katrin Marcus, André Fischer, Paul Lingor

Date Published: 5th Apr 2021

Publication Type: Journal

Systematically defining selective autophagy receptor-specific cargo using autophagosome content profiling.

Abstract (Expand)

Autophagy deficiency in fed conditions leads to the formation of protein inclusions highlighting the contribution of this lysosomal delivery route to cellular proteostasis. Selective autophagy pathways … exist that clear accumulated and aggregated ubiquitinated proteins. Receptors for this type of autophagy (aggrephagy) include p62, NBR1, TOLLIP, and OPTN, which possess LC3-interacting regions and ubiquitin-binding domains (UBDs), thus working as a bridge between LC3/GABARAP proteins and ubiquitinated substrates. However, the identity of aggrephagy substrates and the redundancy of aggrephagy and related UBD-containing receptors remains elusive. Here, we combined proximity labeling and organelle enrichment with quantitative proteomics to systematically map the autophagic degradome targeted by UBD-containing receptors under basal and proteostasis-challenging conditions in human cell lines. We identified various autophagy substrates, some of which were differentially engulfed by autophagosomal and endosomal membranes via p62 and TOLLIP, respectively. Overall, this resource will allow dissection of the proteostasis contribution of autophagy to numerous individual proteins.

Authors: Susanne Zellner, Martina Schifferer, Christian Behrends

Date Published: 18th Mar 2021

Publication Type: Journal

CRISPR-Mediated Induction of Neuron-Enriched Mitochondrial Proteins Boosts Direct Glia-to-Neuron Conversion.

Abstract (Expand)

Astrocyte-to-neuron conversion is a promising avenue for neuronal replacement therapy. Neurons are particularly dependent on mitochondrial function, but how well mitochondria adapt to the new fate is … unknown. Here, we determined the comprehensive mitochondrial proteome of cortical astrocytes and neurons, identifying about 150 significantly enriched mitochondrial proteins for each cell type, including transporters, metabolic enzymes, and cell-type-specific antioxidants. Monitoring their transition during reprogramming revealed late and only partial adaptation to the neuronal identity. Early dCas9-mediated activation of genes encoding mitochondrial proteins significantly improved conversion efficiency, particularly for neuron-enriched but not astrocyte-enriched antioxidant proteins. For example, Sod1 not only improves the survival of the converted neurons but also elicits a faster conversion pace, indicating that mitochondrial proteins act as enablers and drivers in this process. Transcriptional engineering of mitochondrial proteins with other functions improved reprogramming as well, demonstrating a broader role of mitochondrial proteins during fate conversion.

Authors: Gianluca L Russo, Giovanna Sonsalla, Poornemaa Natarajan, Christopher T Breunig, Giorgia Bulli, Juliane Merl-Pham, Sabine Schmitt, Jessica Giehrl-Schwab, Florian Giesert, Martin Jastroch, Hans Zischka, Wolfgang Wurst, Stefan H Stricker, Stefanie M Hauck, Giacomo Masserdotti, Magdalena Götz

Date Published: 4th Mar 2021

Publication Type: Journal

Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia.

Abstract (Expand)

Niemann-Pick type C disease is a rare neurodegenerative disorder mainly caused by mutations in NPC1, resulting in abnormal late endosomal/lysosomal lipid storage. Although microgliosis is a prominent … pathological feature, direct consequences of NPC1 loss on microglial function remain not fully characterized. We discovered pathological proteomic signatures and phenotypes in NPC1-deficient murine models and demonstrate a cell autonomous function of NPC1 in microglia. Loss of NPC1 triggers enhanced phagocytic uptake and impaired myelin turnover in microglia that precede neuronal death. Npc1(-/-) microglia feature a striking accumulation of multivesicular bodies and impaired trafficking of lipids to lysosomes while lysosomal degradation function remains preserved. Molecular and functional defects were also detected in blood-derived macrophages of NPC patients that provide a potential tool for monitoring disease. Our study underscores an essential cell autonomous role for NPC1 in immune cells and implies microglial therapeutic potential.

Authors: A. Colombo, L. Dinkel, S. A. Muller, L. Sebastian Monasor, M. Schifferer, L. Cantuti-Castelvetri, J. Konig, L. Vidatic, T. Bremova-Ertl, A. P. Lieberman, S. Hecimovic, M. Simons, S. F. Lichtenthaler, M. Strupp, S. A. Schneider, S. Tahirovic

Date Published: 24th Feb 2021

Publication Type: Journal

Adult neural stem cell activation in mice is regulated by the day/night cycle and intracellular calcium dynamics.

Abstract (Expand)

Neural stem cells (NSCs) in the adult brain transit from the quiescent state to proliferation to produce new neurons. The mechanisms regulating this transition in freely behaving animals are, however, … poorly understood. We customized in vivo imaging protocols to follow NSCs for several days up to months, observing their activation kinetics in freely behaving mice. Strikingly, NSC division is more frequent during daylight and is inhibited by darkness-induced melatonin signaling. The inhibition of melatonin receptors affected intracellular Ca<sup>2+</sup> dynamics and promoted NSC activation. We further discovered a Ca<sup>2+</sup> signature of quiescent versus activated NSCs and showed that several microenvironmental signals converge on intracellular Ca<sup>2+</sup> pathways to regulate NSC quiescence and activation. In vivo NSC-specific optogenetic modulation of Ca<sup>2+</sup> fluxes to mimic quiescent-state-like Ca<sup>2+</sup> dynamics in freely behaving mice blocked NSC activation and maintained their quiescence, pointing to the regulatory mechanisms mediating NSC activation in freely behaving animals.

Authors: Archana Gengatharan, Sarah Malvaut, Alina Marymonchyk, Majid Ghareghani, Marina Snapyan, Judith Fischer-Sternjak, Jovica Ninkovic, Magdalena Götz, Armen Saghatelyan

Date Published: 4th Feb 2021

Publication Type: Journal

Phagocyte-mediated synapse removal in cortical neuroinflammation is promoted by local calcium accumulation.

Abstract (Expand)

Cortical pathology contributes to chronic cognitive impairment of patients suffering from the neuroinflammatory disease multiple sclerosis (MS). How such gray matter inflammation affects neuronal … structure and function is not well understood. In the present study, we use functional and structural in vivo imaging in a mouse model of cortical MS to demonstrate that bouts of cortical inflammation disrupt cortical circuit activity coincident with a widespread, but transient, loss of dendritic spines. Spines destined for removal show local calcium accumulations and are subsequently removed by invading macrophages or activated microglia. Targeting phagocyte activation with a new antagonist of the colony-stimulating factor 1 receptor prevents cortical synapse loss. Overall, our study identifies synapse loss as a key pathological feature of inflammatory gray matter lesions that is amenable to immunomodulatory therapy.

Authors: Mehrnoosh Jafari, Adrian-Minh Schumacher, Nicolas Snaidero, Emily M Ullrich Gavilanes, Tradite Neziraj, Virág Kocsis-Jutka, Daniel Engels, Tanja Jürgens, Ingrid Wagner, Juan Daniel Flórez Weidinger, Stephanie S Schmidt, Eduardo Beltrán, Nellwyn Hagan, Lisa Woodworth, Dimitry Ofengeim, Joseph Gans, Fred Wolf, Mario Kreutzfeldt, Ruben Portugues, Doron Merkler, Thomas Misgeld, Martin Kerschensteiner

Date Published: 25th Jan 2021

Publication Type: Journal

An optimized quantitative proteomics method establishes the cell type-resolved mouse brain secretome.

Abstract (Expand)

To understand how cells communicate in the nervous system, it is essential to define their secretome, which is challenging for primary cells because of large cell numbers being required. Here, we … miniaturized secretome analysis by developing the "high-performance secretome protein enrichment with click sugars" (hiSPECS) method. To demonstrate its broad utility, hiSPECS was used to identify the secretory response of brain slices upon LPS-induced neuroinflammation and to establish the cell type-resolved mouse brain secretome resource using primary astrocytes, microglia, neurons, and oligodendrocytes. This resource allowed mapping the cellular origin of CSF proteins and revealed that an unexpectedly high number of secreted proteins in vitro and in vivo are proteolytically cleaved membrane protein ectodomains. Two examples are neuronally secreted ADAM22 and CD200, which we identified as substrates of the Alzheimer-linked protease BACE1. hiSPECS and the brain secretome resource can be widely exploited to systematically study protein secretion and brain function and to identify cell type-specific biomarkers for CNS diseases.

Authors: J. Tushaus, S. A. Muller, E. S. Kataka, J. Zaucha, L. Sebastian Monasor, M. Su, G. Guner, G. Jocher, S. Tahirovic, D. Frishman, M. Simons, S. F. Lichtenthaler

Date Published: 15th Oct 2020

Publication Type: Journal

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