Suppression of astrocyte BMP signaling improves fragile X syndrome molecular signatures and functional deficits.

Autor:	Deng J; Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA.; Medical Scientist Training Program, University of California, San Diego, La Jolla, CA, USA.; Neurosciences Graduate Program, University of California, San Diego, La Jolla, CA, USA., Labarta-Bajo L; Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA., Brandebura AN; Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA., Kahn SB; Department of Biology, University of California, San Diego, La Jolla, CA, USA., Pinto AFM; Mass Spectrometry Core for Proteomics and Metabolomics, Salk Institute for Biological Studies, La Jolla, CA, USA., Diedrich JK; Mass Spectrometry Core for Proteomics and Metabolomics, Salk Institute for Biological Studies, La Jolla, CA, USA., Allen NJ; Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Jun 24. Date of Electronic Publication: 2024 Jun 24.
DOI:	10.1101/2024.06.19.599752
Abstrakt:	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. Competing Interests: Competing Interests The authors have no competing interests to declare.
Databáze:	MEDLINE
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