Suppression of astrocyte BMP signaling improves fragile X syndrome molecular signatures and functional deficits.
James DengLara Labarta-BajoAshley N BrandeburaSamuel B KahnAntonio F M PintoJolene K DiedrichNicola J AllenPublished in: bioRxiv : the preprint server for biology (2024)
Fragile X syndrome (FXS) is a monogenic neurodevelopmental disorder with manifestations spanning molecular, neuroanatomical, and behavioral changes. Astrocytes contribute to FXS pathogenesis and show hundreds of dysregulated genes and proteins; targeting upstream pathways mediating astrocyte changes in FXS could therefore be a point of intervention. To address this, we focused on the bone morphogenetic protein (BMP) pathway, which is upregulated in FXS astrocytes. We generated a conditional KO (cKO) of Smad4 in astrocytes to suppress BMP signaling, and found this lessens audiogenic seizure severity in FXS mice. To ask how this occurs on a molecular level, we performed in vivo transcriptomic and proteomic profiling of cortical astrocytes, finding upregulation of metabolic pathways, and downregulation of secretory machinery and secreted proteins in FXS astrocytes, with these alterations no longer present when BMP signaling is suppressed. Functionally, astrocyte Smad4 cKO restores deficits in inhibitory synapses present in FXS auditory cortex. Thus, astrocytes contribute to FXS molecular and functional phenotypes, and targeting astrocytes can mitigate FXS symptoms.
Keyphrases
- mesenchymal stem cells
- traumatic brain injury
- randomized controlled trial
- epithelial mesenchymal transition
- single molecule
- single cell
- poor prognosis
- bone regeneration
- transforming growth factor
- case report
- depressive symptoms
- drug delivery
- skeletal muscle
- metabolic syndrome
- working memory
- high fat diet induced
- physical activity
- long non coding rna
- insulin resistance
- rna seq
- label free