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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE324086 | GEO | 2026/06/26

REPOSITORIES: GEO

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Project description:Abnormal accumulation of aggregated proteins and sustained microglial activation are important contributors of neurodegenerative process in neurological diseases. Recent studies have shown that aggregation-prone proteins, such as a-synuclein, the protein implicated in Parkinson’s disease (PD), are released from neuronal cells and thus present in the extracellular fluid, pointing to the possible paracrine effects of these proteins on microglial immune responses. However, the mechanism underlying the disease-associated microglial activation and the role of neuronal proteins in this process remain unknown. Here, we show that extracellular a-synuclein released from neuronal cells is an endogenous ligand of toll-like receptor 2 (TLR2) and activates microglia, which in turn induces neurodegeneration. Interaction between neuron-released a-synuclein and TLR2 and subsequent activation of the TLR2 signaling were demonstrated comprehensively by using computational modeling of signaling network and by the experimental validation in TLR2-deficient microglia both in vitro and in vivo. In contrast to the neuron-released a-synuclein, recombinant a-synuclein proteins, including monomer, oligomer, fibril, or nitrated forms, were not able to interact or activate TLR2, suggesting that neuronal cells have a mechanism of enriching specific forms of a-synuclein capable of activating TLR2 during the process of releasing this protein. Taken together, the results suggest that both neuron-released extracellular a-synuclein and TLR2 might be novel therapeutic targets for modifying neuroinflammation in PD and related neurodegenerative diseases. We collected culture media from differentiated SH-SY5Y cells overexpressing either human a-synuclein (alpha-SCM) or beta-galactosidase (LZCM) and treat these media to primary rat microglia at the concentration of a-synuclein of 1.1M. Transcriptome analyses with microglial cells treated with either aSCM or LZCM at two different time points, 6 h and 24 h.

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

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