Filter and export

Publications

What is a Publication?
16 Publications visible to you, out of a total of 16
Parkinson's disease motor symptoms rescue by CRISPRa-reprogramming astrocytes into GABAergic neurons.

Abstract (Expand)

Direct reprogramming based on genetic factors resembles a promising strategy to replace lost cells in degenerative diseases such as Parkinson's disease. For this, we developed a knock-in mouse line … carrying a dual dCas9 transactivator system (dCAM) allowing the conditional in vivo activation of endogenous genes. To enable a translational application, we additionally established an AAV-based strategy carrying intein-split-dCas9 in combination with activators (AAV-dCAS). Both approaches were successful in reprogramming striatal astrocytes into induced GABAergic neurons confirmed by single-cell transcriptome analysis of reprogrammed neurons in vivo. These GABAergic neurons functionally integrate into striatal circuits, alleviating voluntary motor behavior aspects in a 6-OHDA Parkinson's disease model. Our results suggest a novel intervention strategy beyond the restoration of dopamine levels. Thus, the AAV-dCAS approach might enable an alternative route for clinical therapies of Parkinson's disease.

Authors: Jessica Giehrl-Schwab, Florian Giesert, Benedict Rauser, Chu Lan Lao, Sina Hembach, Sandrine Lefort, Ignacio L Ibarra, Christina Koupourtidou, Malte Daniel Luecken, Dong-Jiunn Jeffery Truong, Judith Fischer-Sternjak, Giacomo Masserdotti, Nilima Prakash, Jovica Ninkovic, Sabine M Hölter, Daniela M Vogt Weisenhorn, Fabian J Theis, Magdalena Götz, Wolfgang Wurst

Date Published: 9th May 2022

Publication Type: Journal

Innate Immune Pathways Promote Oligodendrocyte Progenitor Cell Recruitment to the Injury Site in Adult Zebrafish Brain.

Abstract (Expand)

The oligodendrocyte progenitors (OPCs) are at the front of the glial reaction to the traumatic brain injury. However, regulatory pathways steering the OPC reaction as well as the role of reactive OPCs … remain largely unknown. Here, we compared a long-lasting, exacerbated reaction of OPCs to the adult zebrafish brain injury with a timely restricted OPC activation to identify the specific molecular mechanisms regulating OPC reactivity and their contribution to regeneration. We demonstrated that the influx of the cerebrospinal fluid into the brain parenchyma after injury simultaneously activates the toll-like receptor 2 (Tlr2) and the chemokine receptor 3 (Cxcr3) innate immunity pathways, leading to increased OPC proliferation and thereby exacerbated glial reactivity. These pathways were critical for long-lasting OPC accumulation even after the ablation of microglia and infiltrating monocytes. Importantly, interference with the Tlr1/2 and Cxcr3 pathways after injury alleviated reactive gliosis, increased new neuron recruitment, and improved tissue restoration.

Authors: Rosario Sanchez-Gonzalez, Christina Koupourtidou, Tjasa Lepko, Alessandro Zambusi, Klara Tereza Novoselc, Tamara Durovic, Sven Aschenbroich, Veronika Schwarz, Christopher T Breunig, Hans Straka, Hagen B Huttner, Martin Irmler, Johannes Beckers, Wolfgang Wurst, Andreas Zwergal, Tamas Schauer, Tobias Straub, Tim Czopka, Dietrich Trümbach, Magdalena Götz, Stefan H Stricker, Jovica Ninkovic

Date Published: 2nd Feb 2022

Publication Type: Journal

Molecular diversity of diencephalic astrocytes reveals adult astrogenesis regulated by Smad4.

Abstract (Expand)

Astrocytes regulate brain-wide functions and also show region-specific differences, but little is known about how general and region-specific functions are aligned at the single-cell level. To explore … this, we isolated adult mouse diencephalic astrocytes by ACSA-2-mediated magnetic-activated cell sorting (MACS). Single-cell RNA-seq revealed 7 gene expression clusters of astrocytes, with 4 forming a supercluster. Within the supercluster, cells differed by gene expression related to ion homeostasis or metabolism, with the former sharing gene expression with other regions and the latter being restricted to specific regions. All clusters showed expression of proliferation-related genes, and proliferation of diencephalic astrocytes was confirmed by immunostaining. Clonal analysis demonstrated low level of astrogenesis in the adult diencephalon, but not in cerebral cortex grey matter. This led to the identification of Smad4 as a key regulator of diencephalic astrocyte in vivo proliferation and in vitro neurosphere formation. Thus, astrocytes show diverse gene expression states related to distinct functions with some subsets being more widespread while others are more regionally restricted. However, all share low-level proliferation revealing the novel concept of adult astrogenesis in the diencephalon.

Authors: Stefanie Ohlig, Solène Clavreul, Manja Thorwirth, Tatiana Simon-Ebert, Riccardo Bocchi, Sabine Ulbricht, Nirmal Kannayian, Moritz Rossner, Swetlana Sirko, Pawel Smialowski, Judith Fischer-Sternjak, Magdalena Götz

Date Published: 2nd Nov 2021

Publication Type: Journal

Heterogeneity of neurons reprogrammed from spinal cord astrocytes by the proneural factors Ascl1 and Neurogenin2.

Abstract (Expand)

Astrocytes are a viable source for generating new neurons via direct conversion. However, little is known about the neurogenic cascades triggered in astrocytes from different regions of the CNS. Here, … we examine the transcriptome induced by the proneural factors Ascl1 and Neurog2 in spinal cord-derived astrocytes in vitro. Each factor initially elicits different neurogenic programs that later converge to a V2 interneuron-like state. Intriguingly, patch sequencing (patch-seq) shows no overall correlation between functional properties and the transcriptome of the heterogenous induced neurons, except for K-channels. For example, some neurons with fully mature electrophysiological properties still express astrocyte genes, thus calling for careful molecular and functional analysis. Comparing the transcriptomes of spinal cord- and cerebral-cortex-derived astrocytes reveals profound differences, including developmental patterning cues maintained in vitro. These relate to the distinct neuronal identity elicited by Ascl1 and Neurog2 reflecting their developmental functions in subtype specification of the respective CNS region.

Authors: J Kempf, K Knelles, B A Hersbach, D Petrik, T Riedemann, V Bednarova, A Janjic, T Simon-Ebert, W Enard, P Smialowski, M Götz, G Masserdotti

Date Published: 20th Jul 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

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

Trnp1 organizes diverse nuclear membrane-less compartments in neural stem cells.

Abstract (Expand)

TMF1-regulated nuclear protein 1 (Trnp1) has been shown to exert potent roles in neural development affecting neural stem cell self-renewal and brain folding, but its molecular function in the nucleus … is still unknown. Here, we show that Trnp1 is a low complexity protein with the capacity to phase separate. Trnp1 interacts with factors located in several nuclear membrane-less organelles, the nucleolus, nuclear speckles, and condensed chromatin. Importantly, Trnp1 co-regulates the architecture and function of these nuclear compartments in vitro and in the developing brain in vivo. Deletion of a highly conserved region in the N-terminal intrinsic disordered region abolishes the capacity of Trnp1 to regulate nucleoli and heterochromatin size, proliferation, and M-phase length; decreases the capacity to phase separate; and abrogates most of Trnp1 protein interactions. Thus, we identified Trnp1 as a novel regulator of several nuclear membrane-less compartments, a function important to maintain cells in a self-renewing proliferative state.

Authors: Miriam Esgleas, Sven Falk, Ignasi Forné, Marc Thiry, Sonia Najas, Sirui Zhang, Aina Mas-Sanchez, Arie Geerlof, Dierk Niessing, Zefeng Wang, Axel Imhof, Magdalena Götz

Date Published: 17th Aug 2020

Publication Type: Journal

Powered by
 (v.1.15.0)
About FAIRDOM | About SyNergy (Munich Cluster for Systems Neurology) | Funding and Programmes | Credits
Copyright © 2008 - 2024 The University of Manchester and HITS gGmbH