Duncan NRI Faculty and Staff Publications
Language
English
Publication Date
7-3-2023
Journal
Nature Communications
DOI
10.1038/s41467-023-39643-7
PMID
37400440
PMCID
PMC10317969
PubMedCentral® Posted Date
7-3-2023
PubMedCentral® Full Text Version
Post-print
Abstract
Batten disease, one of the most devastating types of neurodegenerative lysosomal storage disorders, is caused by mutations in CLN3. Here, we show that CLN3 is a vesicular trafficking hub connecting the Golgi and lysosome compartments. Proteomic analysis reveals that CLN3 interacts with several endo-lysosomal trafficking proteins, including the cation-independent mannose 6 phosphate receptor (CI-M6PR), which coordinates the targeting of lysosomal enzymes to lysosomes. CLN3 depletion results in mis-trafficking of CI-M6PR, mis-sorting of lysosomal enzymes, and defective autophagic lysosomal reformation. Conversely, CLN3 overexpression promotes the formation of multiple lysosomal tubules, which are autophagy and CI-M6PR-dependent, generating newly formed proto-lysosomes. Together, our findings reveal that CLN3 functions as a link between the M6P-dependent trafficking of lysosomal enzymes and lysosomal reformation pathway, explaining the global impairment of lysosomal function in Batten disease.
Keywords
Humans, Membrane Glycoproteins, Neuronal Ceroid-Lipofuscinoses, Receptor, IGF Type 2, Proteomics, Molecular Chaperones, Lysosomes, Hydrolases, Autophagy, Mechanisms of disease, Lysosomes, Golgi
Published Open-Access
yes
Recommended Citation
Calcagni', Alessia; Staiano, Leopoldo; Zampelli, Nicolina; et al., "Loss of the Batten Disease Protein CLN3 Leads to Mis-Trafficking of M6PR and Defective Autophagic-Lysosomal Reformation" (2023). Duncan NRI Faculty and Staff Publications. 43.
https://digitalcommons.library.tmc.edu/duncar_nri_pub/43
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