Astrocytic ACSBG1 depletion improves lipid-cytokine signaling and attenuates α-Synuclein pathology in a Parkinson's disease mouse model

Abstract

Astrocytes are key regulators of lipid metabolism, and dysregulated astrocytic lipid processing is implicated in Parkinsons disease (PD) pathogenesis. Our prior genome-wide screens identified ACSBG1, an astrocyte-enriched acyl-CoA synthetase, as a candidate regulator of -synuclein (-Syn) levels. However, how ACSBG1 links lipid reprogramming to inflammatory astrocyte activation and -Syn pathology remains unknown. We compared the transcriptomic, cytokine, and lipid secretomes of TNF- and IL-1 stimulated primary astrocytes from wild-type (WT) and Acsbg1 knockout (KO) mice. In vivo, we crossed Acsbg1 KO mice with a Thy1--Syn PD model to assess behavior, neuroinflammation, synaptic integrity, and -Syn levels. Following cytokine exposure, Acsbg1 KO astrocytes mounted an attenuated inflammatory transcriptional response, secreting significantly fewer inflammatory mediators (e.g., IL-6, RANTES, MIP-3) and less long-chain Sphingosine 20:1 than WT astrocytes. Importantly, exogenous Sphingosine 20:1 or cytokines from WT reactive astrocytes induced neuronal -Syn phosphorylation (pS129). In vivo, Acsbg1 deletion in Thy1--Syn mice reduced astrogliosis, rescued synaptic and behavioral deficits, and decreased total and pS129--Syn. These findings establish ACSBG1 as a key regulator of inflammatory astrocyte signaling that contributes to -Syn phosphorylation via specific cytokine and lipid mediators, identifying ACSBG1 as a novel therapeutic target for modulating astrocyte-neuron communication in PD. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/726454v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@150a3e3org.highwire.dtl.DTLVardef@137b5caorg.highwire.dtl.DTLVardef@7fe373org.highwire.dtl.DTLVardef@2d996e_HPS_FORMAT_FIGEXP M_FIG C_FIG