Lysosomal Proteomics Links Disturbances in Lipid Homeostasis and Sphingolipid Metabolism to CLN5 Disease

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Doccini , S , Marchese , M , Morani , F , Gamaldi , N , Mero , S , Pezzini , F , Soliymani , R , Santi , M , Signore , G , Ogi , A , Rocchiccioli , S , Kanninen , K M , Simonati , A , Lalowski , M & Santorelli , F M 2022 , ' Lysosomal Proteomics Links Disturbances in Lipid Homeostasis and Sphingolipid Metabolism to CLN5 Disease ' , Cells , vol. 11 , no. 11 , 1840 . https://doi.org/10.3390/cells11111840

Title: Lysosomal Proteomics Links Disturbances in Lipid Homeostasis and Sphingolipid Metabolism to CLN5 Disease
Author: Doccini, Stefano; Marchese, Maria; Morani, Federica; Gamaldi, Nicola; Mero, Serena; Pezzini, Francesco; Soliymani, Rabah; Santi, Melissa; Signore, Giovanni; Ogi, Asahi; Rocchiccioli, Silvia; Kanninen, Katja M.; Simonati, Alessandro; Lalowski, Maciej; Santorelli, Filippo Maria
Contributor organization: Department of Biochemistry and Developmental Biology
Date: 2022-06-04
Language: eng
Number of pages: 17
Belongs to series: Cells
ISSN: 2073-4409
DOI: https://doi.org/10.3390/cells11111840
URI: http://hdl.handle.net/10138/346306
Abstract: CLN5 disease (MIM: 256731) represents a rare late-infantile form of neuronal ceroid lipofuscinosis (NCL), caused by mutations in the CLN5 gene that encodes the CLN5 protein (CLN5p), whose physiological roles stay unanswered. No cure is currently available for CLN5 patients and the opportunities for therapies are lagging. The role of lysosomes in the 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 and highlighted mutual NCL biomarkers scored with high lysosomal confidence. A newly generated cln5 knockdown zebrafish model recapitulated most of the pathological features seen in NCL disease. To translate the findings from in-vitro and preclinical models to patients, we evaluated whether two FDA-approved drugs promoting autophagy via TFEB activation or inhibition of the glucosylceramide synthase could modulate in-vitro ROS and lipid overproduction, as well as alter the locomotor phenotype in zebrafish. In summary, our data advance the general understanding of disease mechanisms and modifying factors in CLN5 disease, which are recurring in other NCL forms, also stimulating new pharmacological treatments.
Subject: 1182 Biochemistry, cell and molecular biology
NCL
CLN5 disease
lysosomes
lysosomal proteomics
trehalose
miglustat
NCL
CLN5 disease
lysosomes
lysosomal proteomics
trehalose
miglustat
NEURONAL CEROID-LIPOFUSCINOSES
PROTEIN
ZEBRAFISH
ALPHA
MODEL
NEUROPATHOLOGY
DEGRADATION
INTERACTOME
DEFICIENCY
ACTIVATION
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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