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@ARTICLE{OualiAlami:164314,
author = {Ouali Alami, Najwa and Tang, Linyun and Wiesner, Diana and
Commisso, Barbara and Bayer, David and Weishaupt, Jochen H
and Dupuis, Luc and Wong, Phillip and Baumann, Bernd and
Wirth, Thomas and Böckers, Tobias and Yilmazer-Hanke, Deniz
and Ludolph, Albert and Roselli, Francesco},
title = {{M}ultiplexed chemogenetics in astrocytes and motoneurons
restore blood–spinal cord barrier in {ALS}},
journal = {Life science alliance},
volume = {3},
number = {11},
issn = {2575-1077},
address = {Heidelberg},
publisher = {EMBO Press},
reportid = {DZNE-2022-00968},
pages = {e201900571},
year = {2020},
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.},
keywords = {Amyotrophic Lateral Sclerosis: blood / Amyotrophic Lateral
Sclerosis: metabolism / Animals / Astrocytes: metabolism /
Astrocytes: physiology / Disease Models, Animal / Disease
Progression / Female / Humans / Male / Mice / Mice, Inbred
C57BL / Mice, Transgenic / Motor Neurons: metabolism / Motor
Neurons: physiology / Spinal Cord: metabolism / Spine: blood
supply / Spine: metabolism / Superoxide Dismutase:
metabolism / Superoxide Dismutase-1: genetics / Superoxide
Dismutase-1: metabolism / Wnt Proteins: metabolism / Wnt-5a
Protein: metabolism},
cin = {AG Roselli / AG Böckers / Clinical Study Center Ulm},
ddc = {570},
cid = {I:(DE-2719)1910001 / I:(DE-2719)1910002 /
I:(DE-2719)5000077},
pnm = {899 - ohne Topic (POF4-899)},
pid = {G:(DE-HGF)POF4-899},
typ = {PUB:(DE-HGF)16},
pmc = {pmc:PMC7479971},
pubmed = {pmid:32900826},
doi = {10.26508/lsa.201900571},
url = {https://pub.dzne.de/record/164314},
}