Hyperactivity of the non-canonical inflammasome promotes neuroinflammation in Hereditary Spastic Paraplegia type SPG11 and SPG48

ABSTRACT: Hereditary spastic paraplegia (HSP) is characterized by a spastic gait disorder due to degeneration of corticospinal axons. The genetics of this disease is highly heterogeneous with more than 80 different genes involved which are denoted as SPGs. Variants in SPG11 are responsible for the most common autosomal recessive HSP also known as SPG11. Its gene product Spatacsin interacts with the adaptor protein 5 complex (AP5), which is presumed to function in membrane trafficking, but pathways and cargoes are largely elusive. Because neurodegeneration in SPG11 is accompanied by marked neuroinflammation, we considered that Spatacsin may play a cell-autonomous role in proinflammatory cell types. Thus, its disruption may perpetuate neuroinflammation and disease progression. Here, we show that Spg11 KO mice display a more pronounced activation of microglia upon systemic challenge with Lipopolysaccharide (LPS). Our subsequent studies in primary microglia and bone marrow derived macrophages (BMDMs) demonstrate that the activation of the non-canonical inflammasome results in a much stronger inflammatory response in Spg11 KO cells, while the canonical pathway is unaffected. These findings are also observed in monocyte-derived macrophages isolated from patients carrying loss-of-function variants in SPG11. In vivo, LPS triggers a much stronger inflammatory response and leads to drastically increased lethality in Spg11 KO mice. Mass spectrometry of activated BMDMs unveils a massive downregulation of AP5 subunits upon disruption of Spg11. Notably, the disruption of its ζ-subunit Ap5z1, which is associated with SPG48, also sensitizes the non-canonical inflammasome. Altogether, our findings provide novel insights into the pathophysiology of SPG11 and SPG48 and suggest that patients with loss-of-function variants in SPG11 or SPG48 may be prone for severe systemic inflammation and organ dysfunction upon infection with Gram-negative bacteria.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Femur, Tibia, Macrophage

SUBMITTER: Robert Hardt  

LAB HEAD: Christian Andreas Hübner

PROVIDER: PXD065699 | Pride | 2025-11-11

REPOSITORIES: Pride