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

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.