Multiplexed chemogenetics in astrocytes and motoneurons restore blood–spinal cord barrier in ALS
| Autor: | Phillip C. Wong, Diana Wiesner, Francesco Roselli, Tobias M. Boeckers, Deniz Yilmazer-Hanke, Barbara Commisso, Linyun Tang, Albert C. Ludolph, Jochen H. Weishaupt, Najwa Ouali Alami, Luc Dupuis, David Bayer, Bernd Baumann, Thomas Wirth |
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| Přispěvatelé: | University of Ulm (UUlm), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Johns Hopkins University School of Medicine [Baltimore], Dieterle, Stéphane |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male [SDV]Life Sciences [q-bio] Health Toxicology and Mutagenesis blood supply [Spine] Plant Science metabolism [Spine] MESH: Spinal Cord Pathogenesis blood [Amyotrophic Lateral Sclerosis] Mice Superoxide Dismutase-1 0302 clinical medicine TANK-binding kinase 1 MESH: Animals Amyotrophic lateral sclerosis MESH: Amyotrophic Lateral Sclerosis MESH: Superoxide Dismutase Research Articles MESH: Superoxide Dismutase-1 Motor Neurons metabolism [Superoxide Dismutase-1] Ecology metabolism [Astrocytes] Chemistry Chemogenetics Cell biology genetics [Superoxide Dismutase-1] [SDV] Life Sciences [q-bio] MESH: Wnt Proteins WNT5A medicine.anatomical_structure Spinal Cord Disease Progression MESH: Disease Progression Female MESH: Spine MESH: Motor Neurons physiology [Motor Neurons] Research Article metabolism [Spinal Cord] Cord MESH: Mice Transgenic metabolism [Superoxide Dismutase] Mice Transgenic Biochemistry Genetics and Molecular Biology (miscellaneous) Wnt-5a Protein 03 medical and health sciences metabolism [Wnt Proteins] MESH: Mice Inbred C57BL ddc:570 medicine Animals Humans MESH: Mice MESH: Humans Superoxide Dismutase metabolism [Amyotrophic Lateral Sclerosis] Amyotrophic Lateral Sclerosis metabolism [Motor Neurons] physiology [Astrocytes] medicine.disease Spinal cord MESH: Wnt-5a Protein Spine MESH: Male Wnt Proteins MESH: Astrocytes Mice Inbred C57BL Disease Models Animal 030104 developmental biology WNT7A Astrocytes MESH: Disease Models Animal MESH: Female metabolism [Wnt-5a Protein] 030217 neurology & neurosurgery |
| Zdroj: | Life science alliance 3(11), e201900571 (2020). doi:10.26508/lsa.201900571 Life Science Alliance Life Science Alliance, Life Science Alliance LLC, 2020, 3 (11), pp.e201900571. ⟨10.26508/lsa.201900571⟩ Life Science Alliance, 2020, 3 (11), pp.e201900571. ⟨10.26508/lsa.201900571⟩ |
| ISSN: | 2575-1077 |
| DOI: | 10.26508/lsa.201900571 |
| Popis: | Chemogenetic motoneuron excitation and astrocyte GPCR-Gi signaling restore blood–spinal cord barrier, disrupted in four ALS mouse models, revealing its role in disease progression but not initiation. Blood–spinal cord barrier (BSCB) disruption is thought to contribute to motoneuron (MN) loss in amyotrophic lateral sclerosis (ALS). It is currently unclear whether impairment of the BSCB is the cause or consequence of MN dysfunction and whether its restoration may be directly beneficial. We revealed that SOD1G93A, FUSΔNLS, TDP43G298S, and Tbk1+/− ALS mouse models commonly shared alterations in the BSCB, unrelated to motoneuron loss. We exploit PSAM/PSEM chemogenetics in SOD1G93A mice to demonstrate that the BSCB is rescued by increased MN firing, whereas inactivation worsens it. Moreover, we use DREADD chemogenetics, alone or in multiplexed form, to show that activation of Gi signaling in astrocytes restores BSCB integrity, independently of MN firing, with no effect on MN disease markers and dissociating them from BSCB disruption. We show that astrocytic levels of the BSCB stabilizers Wnt7a and Wnt5a are decreased in SOD1G93A mice and strongly enhanced by Gi signaling, although further decreased by MN inactivation. Thus, we demonstrate that BSCB impairment follows MN dysfunction in ALS pathogenesis but can be reversed by Gi-induced expression of astrocytic Wnt5a/7a. |
| Databáze: | OpenAIRE |
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