PXD044833-2

PXD044833 is an original dataset announced via ProteomeXchange.

Title	Severe kidney dysfunction in sialidosis mice reveals an essential role for neuraminidase 1 in reabsorption
Description	Sialidosis is an ultrarare multisystemic lysosomal disease caused by mutations in the neuraminidase 1 (NEU1) gene. The severe Type II form of the disease, manifests with a prenatal/infantile or juvenile onset, bone abnormalities, severe neuropathology and visceromegaly. A subset of these patients presents with nephrosialidosis, characterized by abrupt onset of fulminant glomerular nephropathy. We studied the pathophysiological mechanism of the disease in two NEU1-deficient mouse models, a constitutive Neu1 knockout Neu1ΔEx3 and a conditional phagocyte-specific knockout Neu1Cx3cr1ΔEx3. Mice of both strains exhibited terminal urinary retention and severe kidney damage with elevated urinary albumin levels, loss of nephrons, renal fibrosis, presence of storage vacuoles and dysmorphic mitochondria in the intraglomerular and tubular cells. Glycoprotein sialylation in glomeruli, proximal and distal tubules was drastically increased including that of an endocytic reabsorption receptor megalin. The pool of megalin bearing O-linked glycans with terminal galactose residues, essential for protein targeting and activity, was reduced to below detection levels. Megalin levels were severely reduced, and the protein was directed to lysosomes instead of the apical membrane. Together, our results demonstrated that desialylation by NEU1 plays a crucial role in processing and cellular trafficking of megalin and that NEU1 deficiency in sialidosis impairs megalinmediated protein reabsorption.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:25:11.098.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD044833
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Eric Bonneil
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue; acetylated residue; monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2023-08-24 10:56:53	ID requested
1	2024-01-26 06:18:08	announced
⏵ 2	2024-10-22 06:25:19	announced	2024-10-22: Updated project metadata.

Kho I, Demina EP, Pan X, Londono I, Cairo CW, Sturiale L, Palmigiano A, Messina A, Garozzo D, Ung RV, Mac-Way F, Bonneil É, Thibault P, Lemaire M, Morales CR, Pshezhetsky AV, Severe kidney dysfunction in sialidosis mice reveals an essential role for neuraminidase 1 in reabsorption. JCI Insight, 8(20):(2023) [pubmed]

10.6019/PXD044833;

10.1172/jci.insight.166470;

submitter keyword: sialidosis,renal reabsorption, neuraminidase 1, protein sialylation

Alexey V. Pshezhetsky
contact affiliation	Centre de Recherche du CHU Ste-Justine
contact email	alexei.pchejetski@umontreal.ca
lab head
Eric Bonneil
contact affiliation	Proteomic Platform
contact email	eric.bonneil@umontreal.ca
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD044833
     1. Label: PRIDE project
     2. Name: Severe kidney dysfunction in sialidosis mice reveals an essential role for neuraminidase 1 in reabsorption