MassIVE MSV000084880

Partial Public PXD017356

CLN5 involvement in mitochondrial dysfunction

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Description

CLN5 disease is a rare form of late-infantile neuronal ceroid lipofuscinosis (NCL) caused by mutations in the CLN5 gene that encodes a protein whose primary function and physiological roles remains unresolved. Emerging lines of evidence point to mitochondrial dysfunction in the onset and progression of several forms of NCL, offering new insights into putative biomarkers and shared biological processes. In this work, we employed cellular and murine models of the disease, in an effort to clarify disease pathways associated with CLN5 depletion. A mitochondria-focused quantitative proteomics approach followed by functional validations using cell biology and immunofluorescence assays revealed an impairment of mitochondrial functions in different CLN5 KO cell models and in Cln5 KO cerebral cortex, which well correlated with disease progression. A visible impairment of autophagy machinery coupled with alterations of key parameters of mitophagy activation process functionally linked CLN5 protein to the process of neuronal injury. The functional link between impaired cellular respiration and activation of mitophagy pathways in the human CLN5 disease condition was corroborated by translating organelle specific proteome findings to CLN5 patients fibroblasts. Our study highlights the involvement of CLN5 in activation of mitophagy and mitochondrial homeostasis offering new insights into alternative strategies towards the CLN5 disease treatment. [doi:10.25345/C5PQ4G] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: CLN5 ; disease models ; mitochondrion ; quantitative label free proteomics ; autophagy ; mitophagy

Contact

Principal Investigators:
(in alphabetical order) 		Alessandro Simonati, Universita degli Studi di Verona, Dipartimento di Neuroscienze, Biomedicina e Movimento-Neurologia (Neuropsichiatria Infantile e Neuropatologia), Policlinico GB Rossi, P.le LA Scuro 10, 37134 Verona, Italy, Italy
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

Publications

Stefano Doccini, Federica Morani, Claudia Nesti, Francesco Pezzini, Giulio Calza, Rabah Soliymani, Giovanni Signore, Silvia Rocchiccioli, Katja M. Kanninen, Mikko T. Huuskonen, Marc H. Baumann, Alessandro Simonati, Maciej M. Lalowski & Filippo M. Santorelli.
Proteomic and functional analyses in disease models reveal CLN5 protein involvement in mitochondrial dysfunction.
Cell Death Discov. 6, 18 (2020). doi: 10.1038/s41420-020-0250-y.

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