Loss of ADAP1/CentA1 Protects Against Autoimmune Demyelination

ArfGAP with dual PH domain-containing protein 1 (ADAP1), also known as Centaurin alpha-1 (CentA1), is an actin-binding protein highly expressed in the central nervous system (CNS) that was previously shown to regulate dendritic spine density and plasticity. In the context of disease, ADAP1/CentA1 has been linked to Alzheimer's disease (AD) pathogenesis, cancer progression, and human immunodeficiency virus (HIV) reactivation. Here, we document that ADAP1/CentA1 is also mechanistically involved in CNS autoimmunity. We show that ADAP1/CentA1 deficient mice exhibit partial resistance to developing experimental autoimmune encephalomyelitis (EAE), an in vivo disease model recapitulating several features of multiple sclerosis (MS) pathogenesis. MS is a chronic autoimmune disorder of the CNS characterized by focal immune cell infiltration, demyelination, and axonal injury. Its etiology is still elusive, but genetic and environmental factors contribute to disease risk. By combining detailed immunophenotyping and single-cell RNA sequencing (scRNA-seq), we demonstrate that ADAP1/CentA1 is necessary for mounting a sufficient autoimmune response for EAE initiation and progression. In particular, the current study highlights that ADAP1/CentA1 expression in the immune system mainly targets the functioning of regulatory T cells (Tregs), monocytes, and natural killer (NK) cells. In summary, our study defines a novel function for ADAP/CentA1 outside of the CNS and helps elucidate the early molecular events taking place in the peripheral immune system in response to encephalitogenic challenges.