The 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.
[doi:10.25345/C5HW04]
[dataset license: CC0 1.0 Universal (CC0 1.0)]
Keywords: NCL, CLN5 disease, lysosomes, lysosomal proteomics, trehalose, misglustat
Principal Investigators: (in alphabetical order) |
Filippo M. Santorelli, IRCCS Fondazione Stella Maris, via dei Giacinti 2, 56128 Pisa, Italy Maciej Lalowski, Helsinki Institute for Life Science (HiLIFE) and Faculty of Medicine, Biochemistry/Developmental Biology, Meilahti Clinical Proteomics Core Facility, University of Helsinki, Helsinki, FI-00014, Finland |
Submitting User: | MaciejLalowski_2 |
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.
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