CLEC16A in astrocytes promotes mitophagy and limits pathology in a multiple sclerosis mouse model.

ABSTRACT: Astrocytes promote neuroinflammation and neurodegeneration in multiple sclerosis (MS) through cell-intrinsic activities and their ability to recruit and activate other cell types. In a genome-wide CRISPR-based forward genetic screen investigating regulators of astrocyte proinflammatory responses, we identified the C-type lectin domain-containing 16A gene (CLEC16A), linked to MS susceptibility, as a suppressor of nuclear factor-κB (NF-κB) signaling. Gene and small-molecule perturbation studies in mouse primary and human embryonic stem cell-derived astrocytes in combination with multiomic analyses established that CLEC16A promotes mitophagy, limiting mitochondrial dysfunction and the accumulation of mitochondrial products that activate NF-κB, the NLRP3 inflammasome and gasdermin D. Astrocyte

SUBMITTER: Kadowaki A 

PROVIDER: S-EPMC12039076 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature