PXD065699

PXD065699 is an original dataset announced via ProteomeXchange.

Title	Hyperactivity of the non-canonical inflammasome promotes neuroinflammation in Hereditary Spastic Paraplegia type SPG11 and SPG48
Description	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.
HostingRepository	PRIDE
AnnounceDate	2025-11-11
AnnouncementXML	Submission_2025-11-11_13:50:00.180.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Robert Hardt
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	S-carboxamidoethyl-L-cysteine; acetylated residue; monohydroxylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2025-07-02 16:13:18	ID requested
⏵ 1	2025-11-11 13:50:01	announced

Afzal MA, Ghait M, Hussain A, Siegmund A, Tuchscherr L, Babic P, Press AT, Hardt R, Winter D, R, ö, diger A, Sch, ü, le R, Fielitz J, Bauer M, H, ü, bner CA, Hyperactivity of the non-canonical inflammasome in SPG11 and SPG48. EBioMedicine, 121():105985(2025) [pubmed]

10.1016/j.ebiom.2025.105985;

submitter keyword: neuroinflammation, bone marrow derived macrophages, SPG48,SPG11

Christian Andreas Hübner
contact affiliation	Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Am Klinikum1, 07747 Jena, Germany
contact email	Christian.huebner@med.uni-jena.de
lab head
Robert Hardt
contact affiliation	Institute for Biochemistry and Molecular Biology, Medical Faculty, University of Bonn, 53115 Bonn, Germany
contact email	rhardt@uni-bonn.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD065699
     1. Label: PRIDE project
     2. Name: Hyperactivity of the non-canonical inflammasome promotes neuroinflammation in Hereditary Spastic Paraplegia type SPG11 and SPG48