Hereditary spastic paraplegia (HSP) gene 11 (SPG11) attenuates lipid accumulation in myeloid cells and neuroinflammation independent of α-synuclein pathology

Hereditary spastic paraplegia type 11 (HSP-SPG11) is a neurodegenerative disorder caused by mutations in SPG11, which encodes the large scaffolding protein spatacsin, involved in lysosomal and autophagosomal trafficking. A portion of patients with SPG11 mutations show overlapping clinical presentations with Parkinson’s disease (PD) patients. While spatacsin dysfunction is linked to neurodegeneration, the underlying cellular mechanisms remain largely unclear. Here, we demonstrate that loss of Spg11 results in neuroinflammation and lipid accumulation in myeloid cells, independent of α-synuclein aggregation. Bulk RNA sequencing revealed a strong upregulation of microglial genes in Spg11 knockouts, supported by increased CD68 expression and morphological changes consistent with microglial activation. Spg11 depletion in two in vivo models of PD revealed no enhancement of phosphorylated αSyn-positive inclusions or dopaminergic neuron loss; however, the mice did exhibit Spg11-dependent microglial reactivity. Further in vitro studies using primary bone-derived macrophages revealed increased phagocytic capacity and neutral lipid accumulation under basal and stress conditions. These findings support a model where SPG11 is a critical regulator of microglial activation and myeloid lipid metabolism, contributing to neurodegeneration through pathways distinct from classical α-synuclein-mediated pathology.