PXD054766

PXD054766 is an original dataset announced via ProteomeXchange.

Title	Lipofuscin accumulation in aging and CLN1 is associated with deficient de-S-acylation, lysomitochondrial dysfunction, and lipid dyshomeostasis
Description	Lipofuscin is an autofluorescent material that accrues in brain tissues with age and in Neuronal Ceroid Lipofuscinosis (NCL), a neurodegenerative disease with pediatric onset. The distribution, composition, and organellar origin of lipofuscin have remained unclear despite its widespread presence in aged tissues and involvement in neurodegeneration. Here, we elucidate lipofuscin composition in mouse and human brain and assemble a reference neuroanatomical atlas of lipofuscin accumulation with age and NCL (Type 1; CLN1) progression across 425 fine brain regions. We identify a primary role of the lysosomal-mitochondrial axis in the formation of lipofuscin pathology via multimodal mass spectrometry, ultrastructural analyses, and assays of cellular and enzymatic metabolism. We find the protein and lipid composition of age and CLN1 lipofuscin to be remarkably similar. Dissection of implicated molecular pathways reveals protein Sacylation and unsaturated lipid homeostasis as central processes involved in lipofuscin deposition during aging and CLN1. Notably, >95% of lipofuscin resident proteins can be S-acylated and many are substrates of the enzyme PPT1, validating a seminal hypothesis that CLN1 lipofuscin contains these lipid-modified proteins. Further, we discover deficient de-S-acylation is correlated with lipofuscin load in healthy aging, as the specific de-S-acylation enzyme activity of PPT1 is found to decline with advancing age. Finally, we identify lipid metabolite biomarkers of lipofuscin, including long-chain polyunsaturated fatty acids, bis(monoacylglycerol)phosphate (BMP), and oxidized phosphatidylethanolamine (OxPE) lipid species. Overall, we provide a comprehensive redefinition of lipofuscin neuropathology and a resource for studying aging, lysosomal storage disorders, and neurodegeneration.
HostingRepository	PRIDE
AnnounceDate	2026-05-06
AnnouncementXML	Submission_2026-05-06_14:51:46.133.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	TuKiet Lam
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	phosphorylated residue; acetylated residue; monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Q Exactive Plus

Revision	Datetime	Status	ChangeLog Entry
0	2024-08-09 13:24:01	ID requested
⏵ 1	2026-05-06 14:51:47	announced

10.1007/S00401-026-03012-7;

submitter keyword: None

TuKiet Lam
contact affiliation	Keck MS & Proteomics Resource Yale School of Medicine
contact email	tukiet.lam@yale.edu
lab head
TuKiet Lam
contact affiliation	Yale University
contact email	tukiet.lam@yale.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD054766
     1. Label: PRIDE project
     2. Name: Lipofuscin accumulation in aging and CLN1 is associated with deficient de-S-acylation, lysomitochondrial dysfunction, and lipid dyshomeostasis