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Article

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

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Molecular Medicine–IRCCS Stella Maris, 56128 Pisa, Italy
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Department of Biology, University of Pisa, 56126 Pisa, Italy
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Ph.D. Program in Neuroscience, University of Florence, 50121 Florence, Italy
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Department of Surgery, Dentistry, Paediatrics and Gynaecology, University of Verona, 37129 Verona, Italy
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HiLIFE, Meilahti Clinical Proteomics Core Facility, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland
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NEST, Scuola Normale Superiore and Istituto Nanoscienze-CNR, 56127 Pisa, Italy
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Fondazione Pisana per la Scienza, 56017 Pisa, Italy
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Institute of Clinical Physiology-CNR, 56124 Pisa, Italy
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A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70210 Kuopio, Finland
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Institute of Bioorganic Chemistry, PAS, Department of Biomedical Proteomics, 61-704 Poznan, Poland
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Authors to whom correspondence should be addressed.
Academic Editors: Hans Zempel, Natja Haag and Juliane Bremer
Cells 2022, 11(11), 1840; https://doi.org/10.3390/cells11111840
Received: 29 April 2022 / Revised: 29 May 2022 / Accepted: 1 June 2022 / Published: 4 June 2022
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. View Full-Text
Keywords: NCL; CLN5 disease; lysosomes; lysosomal proteomics; trehalose; miglustat NCL; CLN5 disease; lysosomes; lysosomal proteomics; trehalose; miglustat
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MDPI and ACS Style

Doccini, S.; Marchese, M.; Morani, F.; Gammaldi, N.; Mero, S.; Pezzini, F.; Soliymani, R.; Santi, M.; Signore, G.; Ogi, A.; Rocchiccioli, S.; Kanninen, K.M.; Simonati, A.; Lalowski, M.M.; Santorelli, F.M. Lysosomal Proteomics Links Disturbances in Lipid Homeostasis and Sphingolipid Metabolism to CLN5 Disease. Cells 2022, 11, 1840. https://doi.org/10.3390/cells11111840

AMA Style

Doccini S, Marchese M, Morani F, Gammaldi N, Mero S, Pezzini F, Soliymani R, Santi M, Signore G, Ogi A, Rocchiccioli S, Kanninen KM, Simonati A, Lalowski MM, Santorelli FM. Lysosomal Proteomics Links Disturbances in Lipid Homeostasis and Sphingolipid Metabolism to CLN5 Disease. Cells. 2022; 11(11):1840. https://doi.org/10.3390/cells11111840

Chicago/Turabian Style

Doccini, Stefano, 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, and Filippo M. Santorelli. 2022. "Lysosomal Proteomics Links Disturbances in Lipid Homeostasis and Sphingolipid Metabolism to CLN5 Disease" Cells 11, no. 11: 1840. https://doi.org/10.3390/cells11111840

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