TY  - JOUR
AU  - Ouali Alami, Najwa
AU  - Tang, Linyun
AU  - Wiesner, Diana
AU  - Commisso, Barbara
AU  - Bayer, David
AU  - Weishaupt, Jochen H
AU  - Dupuis, Luc
AU  - Wong, Phillip
AU  - Baumann, Bernd
AU  - Wirth, Thomas
AU  - Böckers, Tobias
AU  - Yilmazer-Hanke, Deniz
AU  - Ludolph, Albert
AU  - Roselli, Francesco
TI  - Multiplexed chemogenetics in astrocytes and motoneurons restore blood–spinal cord barrier in ALS
JO  - Life science alliance
VL  - 3
IS  - 11
SN  - 2575-1077
CY  - Heidelberg
PB  - EMBO Press
M1  - DZNE-2022-00968
SP  - e201900571
PY  - 2020
AB  - 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.
KW  - Amyotrophic Lateral Sclerosis: blood
KW  - Amyotrophic Lateral Sclerosis: metabolism
KW  - Animals
KW  - Astrocytes: metabolism
KW  - Astrocytes: physiology
KW  - Disease Models, Animal
KW  - Disease Progression
KW  - Female
KW  - Humans
KW  - Male
KW  - Mice
KW  - Mice, Inbred C57BL
KW  - Mice, Transgenic
KW  - Motor Neurons: metabolism
KW  - Motor Neurons: physiology
KW  - Spinal Cord: metabolism
KW  - Spine: blood supply
KW  - Spine: metabolism
KW  - Superoxide Dismutase: metabolism
KW  - Superoxide Dismutase-1: genetics
KW  - Superoxide Dismutase-1: metabolism
KW  - Wnt Proteins: metabolism
KW  - Wnt-5a Protein: metabolism
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC7479971
C6  - pmid:32900826
DO  - DOI:10.26508/lsa.201900571
UR  - https://pub.dzne.de/record/164314
ER  -