Formation of CSE-YAP complex drives FOXD3-mediated transition of neurotoxic astrocytes in Parkinson's disease.

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  • Additional Information
    • Source:
      Publisher: Elsevier Country of Publication: Netherlands NLM ID: 8907422 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1096-1186 (Electronic) Linking ISSN: 10436618 NLM ISO Abbreviation: Pharmacol Res Subsets: MEDLINE
    • Publication Information:
      Publication: Oct. 2015- : Amsterdam ; Elsevier
      Original Publication: London ; San Diego : Academic Press, c1989-
    • Subject Terms:
      Astrocytes*/metabolism ; Astrocytes*/drug effects ; Parkinson Disease*/metabolism ; Parkinson Disease*/pathology ; Parkinson Disease*/genetics ; YAP-Signaling Proteins*/metabolism ; YAP-Signaling Proteins*/genetics ; Forkhead Transcription Factors*/metabolism ; Forkhead Transcription Factors*/genetics ; Cystathionine gamma-Lyase*/metabolism ; Cystathionine gamma-Lyase*/genetics; Animals ; Humans ; Male ; Mice, Inbred C57BL ; Mice ; Cells, Cultured ; Female
    • Abstract:
      Astrocytes, constituting the predominant glial cells in the brain, undergo significant morphological and functional transformations amidst the progression of Parkinson's disease (PD). A majority of these reactive astrocytes display a neurotoxic phenotype, intensifying inflammatory responses. Nonetheless, the molecular underpinnings steering neurotoxic astrocyte reactivity during PD progression remain mostly uncharted. Here, we uncover the unique role of cystathionine γ-lyase (CSE) in shaping astrocyte reactivity, primarily channeling astrocytes towards a neurotoxic phenotype, thereby escalating neuroinflammation in PD. Single-cell sequencing data drawn from PD patients coupled with RNA sequencing data from MPP + -treated astrocytes, highlighted a marked positive association between increased expression of Cth, the gene that encodes CSE, and neurotoxic astrocyte reactivity. Employing genetic manipulation of Cth in astrocytes, we evidenced that CSE instigates a transition to a neurotoxic state in PD-afflicted astrocytes under in vitro and in vivo settings. Moreover, we identified a CSE-Yes-associated protein (YAP) complex within astrocytes via label-free mass spectrometry. An increased formation of the CSE-YAP complex was found to facilitate the expression of gene patterns tied to neurotoxic astrocytes, driven by the transcription factor, forkhead box protein D3 (FOXD3). Consequently, our work unveils valuable insights into the cell type-specific function of CSE in the brain, and presents FOXD3 as a novel transcription factor influencing astrocyte phenotypes in PD. These findings lay the groundwork for the development of potential strategies intended to manage conditions associated with neuroinflammation.
      Competing Interests: Declaration of Competing Interest The authors declare no competing interests.
      (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
    • Contributed Indexing:
      Keywords: CSE; FOXD3; Neuroinflammation; Neurotoxic astrocytes; Parkinson’s disease
    • Accession Number:
      0 (YAP-Signaling Proteins)
      0 (Forkhead Transcription Factors)
      EC 4.4.1.1 (Cystathionine gamma-Lyase)
      0 (Yap1 protein, mouse)
      0 (YAP1 protein, human)
    • Publication Date:
      Date Created: 20241115 Date Completed: 20241218 Latest Revision: 20241218
    • Publication Date:
      20241219
    • Accession Number:
      10.1016/j.phrs.2024.107507
    • Accession Number:
      39547464