Journal Article

DZNE-2022-00968

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Multiplexed chemogenetics in astrocytes and motoneurons restore blood–spinal cord barrier in ALS

Ouali Alami, N. ; Tang, L. ; Wiesner, D.DZNE* ; Commisso, B. ; Bayer, D. ; Weishaupt, J. H.Extern* ; Dupuis, L. ; Wong, P. ; Baumann, B. ; Wirth, T. ; Böckers, T.DZNE* ; Yilmazer-Hanke, D. ; Ludolph, A.DZNE* ; Roselli, F. (Last author)DZNE*

2020
EMBO Press Heidelberg

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Please use a persistent id in citations: doi:10.26508/lsa.201900571

Abstract: 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 SOD1 G93A , FUS ΔNLS , TDP43 G298S , and Tbk1 +/- ALS mouse models commonly shared alterations in the BSCB, unrelated to motoneuron loss. We exploit PSAM/PSEM chemogenetics in SOD1 G93A 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 SOD1 G93A 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.

Keyword(s): Amyotrophic Lateral Sclerosis: blood (MeSH) ; Amyotrophic Lateral Sclerosis: metabolism (MeSH) ; Animals (MeSH) ; Astrocytes: metabolism (MeSH) ; Astrocytes: physiology (MeSH) ; Disease Models, Animal (MeSH) ; Disease Progression (MeSH) ; Female (MeSH) ; Humans (MeSH) ; Male (MeSH) ; Mice (MeSH) ; Mice, Inbred C57BL (MeSH) ; Mice, Transgenic (MeSH) ; Motor Neurons: metabolism (MeSH) ; Motor Neurons: physiology (MeSH) ; Spinal Cord: metabolism (MeSH) ; Spine: blood supply (MeSH) ; Spine: metabolism (MeSH) ; Superoxide Dismutase: metabolism (MeSH) ; Superoxide Dismutase-1: genetics (MeSH) ; Superoxide Dismutase-1: metabolism (MeSH) ; Wnt Proteins: metabolism (MeSH) ; Wnt-5a Protein: metabolism (MeSH)

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Contributing Institute(s):

1. Metabolic Changes in Neurodegeneration (AG Roselli)
2. Translational Protein Biochemistry (AG Böckers)
3. Clinical Study Center Ulm (Clinical Study Center Ulm)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2020

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Database coverage:
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