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PXD030188-1

PXD030188 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleLysosomal proteomics links disturbances in lipid homeostasis and sphingolipid metabolism to CLN5 disease.
DescriptionThe CLN5 disease (MIM: 256731) represents a rare late-infantile form of neuronal ceroid lipofuscinosis (NCL) caused by mutations in the CLN5 gene that encodes a CLN5 protein (CLN5p), whose physiological roles remain unanswered. No cure is currently available for CLN5 patients and the opportunities for therapies are lagging behind. The role of lysosomes in neuro-pathophysiology of CLN5 disease represents an important topic since lysosomal proteins are directly involved in the primary mechanisms of neuronal injury occurring in various NCL forms. We developed and implemented a lysosome-focused, label-free quantitative proteomics approach followed by functional validations in both CLN5-knockout neuronal-like cell lines and Cln5-/- mice, to unravel affected pathways and modifying factors involved in this disease -scenario. Our results revealed a key role of CLN5p in lipid homeostasis and sphingolipid metabolism, representing a possible connection to the activation of mitochondria-driven cell death and mitophagy, other features of CLN5 disease. To translate findings from preclinical models to patients, we evaluated in vitro if FDA-approved drugs promoting autophagy via TFEB activation or inhibition of the glucosylceramide synthase could modulate ROS and lipids overproduction. We further tested in vivo, the efficacy of drugs in rescuing the locomotor function in a newly generated cln5 knockdown zebrafish model, recapitulating most of the pathological features seen in NCL. In summary, our data advances general understanding of pathogenetic mechanisms in CLN5 disease, stipulating new pharmacological treatments.
HostingRepositoryMassIVE
AnnounceDate2022-06-05
AnnouncementXMLSubmission_2022-06-05_12:06:57.744.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterMaciej Lalowski
SpeciesList scientific name: Homo sapiens; common name: human; NCBI TaxID: 9606; scientific name: Mus musculus; common name: house mouse; NCBI TaxID: 10090;
ModificationListCarbamidomethyl; Deamidated; Oxidation
InstrumentSynapt G2-S HDMS
Dataset History
RevisionDatetimeStatusChangeLog Entry
02021-12-05 06:51:39ID requested
12022-06-05 12:06:58announced
Publication List
Stefano Doccini*, Maria Marchese, Federica Morani, Nicola Gammaldi, Serena Mero, Francesco Pezzini, Rabah Soliymani, Melissa Santi, Giovanni Signore, Asahi Ogi, Silvia Rocchiccioli, Katja M. Kanninen, Alessandro Simonati, Maciej M. Lalowski*, Filippo M. Santorelli*. Lysosomal Proteomics Links Disturbances in Lipid Homeostasis and Sphingolipid Metabolism to CLN5 Disease. Cells 2022, 11, 1840. https://doi.org/10.3390/cells11111840.
Keyword List
submitter keyword: NCL, CLN5 disease, lysosomes, lysosomal proteomics, trehalose, misglustat
Contact List
Maciej Lalowski
contact affiliationHelsinki Institute for Life Science (HiLIFE) and Faculty of Medicine, Biochemistry/Developmental Biology, Meilahti Clinical Proteomics Core Facility, University of Helsinki, Helsinki, FI-00014
contact emailmaciej.lalowski@helsinki.fi
lab head
Filippo M. Santorelli
contact affiliationIRCCS Fondazione Stella Maris, via dei Giacinti 2, 56128 Pisa
contact emailfilippo3364@gmail.com
lab head
Maciej Lalowski
contact affiliationUniversity of Helsinki/Medicum
contact emailmaciej.lalowski@helsinki.fi
dataset submitter
Full Dataset Link List
MassIVE dataset URI
Dataset FTP location
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