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Multiplexed chemogenetics in astrocytes and motoneurons restore blood–spinal cord barrier in ALS

Authors :
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
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
Source :
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⟩
Publication Year :
2020
Publisher :
EMBO Press, 2020.

Abstract

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.<br />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.

Subjects

Subjects :
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

Details

Language :
English
ISSN :
25751077
Database :
OpenAIRE
Journal :
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⟩
Accession number :
edsair.doi.dedup.....93218dfe1100975b7bc1fb24ea761df4
Full Text :
https://doi.org/10.26508/lsa.201900571