Mucin-type O-glycosylation (O-GalNAcylation) is a structurally diverse post-translational modification (PTM) that serves as a critical molecular interface at the cell surface. Unlike well-characterized PTMs such as phosphorylation or N-glycosylation, the specific roles of O-GalNAcylation in the mammalian brain have long remained poorly understood. Recent studies have begun to reposition this modification as an important regulator of brain architecture and homeostasis. Emerging evidence suggests that it contributes to neuronal organization, neurovascular integrity, synaptic function, and stress-related behavioral phenotypes, and that its dysregulation may be associated with neurological and psychiatric phenotypes. This perspective synthesizes recent advances to highlight the potential importance of a "brain O-glycan code" in brain health and disease. We discuss how remodeling of this glycan landscape may intersect with aging, neuroinflammation, and synaptic plasticity, and propose that glyco-neurobiology provides an additional conceptual layer for understanding brain vulnerability and resilience. Finally, we consider how targeting O-glycosylation pathways may open new avenues for diagnostic and therapeutic strategies in neurodegenerative and psychiatric disease.
Youngsuk Seo, Hyun Joo An, Boyoung Lee· Molecular Psychiatry· 0 citations
Autophagy dysfunction and neuroinflammation are central to Alzheimer’s disease (AD), yet how extracellular amyloid-β (Aβ) couples to impaired autophagic flux and heightened neuroinflammation remains unknown. Here, we identify the TAM receptor AXL as a molecular transducer that couples Aβ sensing to the regulation of autophagy and neuroinflammation in astrocytes. Aβ induces γ-secretase-dependent cleavage of AXL, generating a nuclear intracellular domain (AXL-ICD) that forms phase-separated condensates and activates autophagy gene transcription through SIRT2-mediated recruitment of the RUVBL1/2-INO80 chromatin-remodeling complex. This axis is activated in astrocytes of postmortem AD brains. Concurrently, AXL-ICD binds to the SIRT2 catalytic domain and suppresses its deacetylase activity, increasing α-tubulin acetylation and altering microtubule dynamics. While moderate AXL-ICD levels promote autophagic flux, excessive elevation paradoxically triggers microtubule hyperstabilization, thereby impairing autophagosome-lysosome fusion and causing pathological accumulation of autophagosomes and H2O2. The inhibitory peptide AxSBiP disrupts the AXL-ICD/SIRT2 interaction, restores autophagic flux, reduces plaque burden, and normalizes Aβ-induced H2O2 production and astrogliosis in APP/PS1 mice. We propose the AXL-ICD/SIRT2 axis as an effective therapeutic target to reduce Aβ burden and neuroinflammation in AD.
T. Kim, Mridula Bhalla, Uiyeol Park et al.· bioRxiv· 0 citations
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