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.
Highlights
Disruption of the blood–spinal cord barrier (BSCB) is a recently appreciated feature of amyotrophic lateral sclerosis (ALS), a disease affecting upper and lower motoneurons (MNs) with a progressive course and invariably fatal outcome (Hardiman et al, 2017)
We have showed that (i) BSCB structural and functional disruption is detected in four ALS mouse lines with unrelated mutations and different degrees of MN loss; (ii) the disruption of the BSCB takes place before any MN loss, and it is restored by enhancing MN excitability; and (iii) the activation of Gi signaling in astrocytes reverts the disruption of the BSCB by increasing Wnt5a/Wnt7a expression but without impacting the burden of disease markers in MN and independently of MN firing
The disruption of the BSCB in ALS has been previously reported (Garbuzova-Davis et al, 2007a, 2007b; Zhong et al, 2008), the nature of the primum movens has remained debated: Is BSCB impairment driven by MN dysfunction or is it a MN-independent event? Some evidence has pointed toward an MNindependent origin: Endothelial cells expressing mutant SOD1 in vitro display a cell-autonomous disruption of tight junction (TJ) because of the misfolded protein itself (Meister et al, 2015)
Summary
Disruption of the blood–spinal cord barrier (BSCB) is a recently appreciated feature of amyotrophic lateral sclerosis (ALS), a disease affecting upper and lower motoneurons (MNs) with a progressive course and invariably fatal outcome (Hardiman et al, 2017). In spinal cord samples from ALS patients, BSCB impairment has been detected in the form of plasma protein leakage and reduced expression of endothelial tight junction (TJ) proteins (Garbuzova-Davis et al, 2012). Warfarin (an anticoagulant interfering with multiple vitamin K–dependent coagulation factors) aggravated BSCB disruption and worsened the degeneration of MN (Winkler et al, 2014). None of these interventions are selective and may affect multiple disease cascades at once (e.g., reducing the transcription of the mutant SOD1 gene in the case of APC; Zhong et al, 2009)
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