Astrocyte SigmaR1/UPR/XBP1 Signaling Links Neuroinflammation and Neurodegeneration in XDP and PD

Neurodegenerative movement disorders such as X-linked Dystonia Parkinsonism (XDP) andParkinson’s Disease (PD) share hallmark features of progressive motor impairment andneurodegeneration, yet common pathogenic drivers and therapeutic targets remain poorlydefined. Here, we integrate single-nuclei RNA-seq (snRNA-seq) analysis of XDP and PD patientsamples with patient derived iPSC astrocytes, pre-clinical mouse models, knockout mice, andcell-specific CRISPR/Cas9 perturbations to uncover shared mechanisms of disease pathology. InXDP, we link neuronal stress and degeneration to impaired neuron-astrocyte interactions, anastrocyte subset displaying Sigma-1 Receptor (SigmaR1) signaling, and increased unfoldedprotein response (UPR) / X-Box Binding Protein 1 (XBP1) activation. Pharmacologic SigmaR1inhibition restored homeostasis and reduced pro-inflammatory responses in XDP patient-derivedastrocytes. Remarkably, SigmaR1-driven astrocytes are also enriched in idiopathic PD and itspre-clinical mouse model induced by pre-formed fibril (PFF). Systemic and astrocyte-specificgenetic SigmaR1 inactivation, as well as pharmacological inhibition, limited astrocyte pro-inflammatory responses, preserved dopaminergic neurons, reduced pathologic α-synucleinphosphorylation, and improved motor function in the PFF mouse model. These findings identifyastrocytes controlled by SigmaR1 / UPR / XBP1 signaling as shared drivers of central nervoussystem (CNS) pathology and candidate therapeutic targets in XDP, PD, and potentially otherrelated diseases.