: 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.

Loss of the batten disease protein CLN3 leads to mis-trafficking of M6PR and defective autophagic-lysosomal reformation / Calcagni', Alessia; Staiano, Leopoldo; Zampelli, Nicolina; Minopoli, Nadia; Herz, Niculin J; Di Tullio, Giuseppe; Huynh, Tuong; Monfregola, Jlenia; Esposito, Alessandra; Cirillo, Carmine; Bajic, Aleksandar; Zahabiyon, Mahla; Curnock, Rachel; Polishchuk, Elena; Parkitny, Luke; Medina, Diego Luis; Pastore, Nunzia; Cullen, Peter J; Parenti, Giancarlo; De Matteis, Maria Antonietta; Grumati, Paolo; Ballabio, Andrea. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 14:1(2023), p. 3911. [10.1038/s41467-023-39643-7]

Loss of the batten disease protein CLN3 leads to mis-trafficking of M6PR and defective autophagic-lysosomal reformation

Calcagni', Alessia;Minopoli, Nadia;Monfregola, Jlenia;Medina, Diego Luis;Pastore, Nunzia;Parenti, Giancarlo;De Matteis, Maria Antonietta;Grumati, Paolo;Ballabio, Andrea
2023

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.
2023
Loss of the batten disease protein CLN3 leads to mis-trafficking of M6PR and defective autophagic-lysosomal reformation / Calcagni', Alessia; Staiano, Leopoldo; Zampelli, Nicolina; Minopoli, Nadia; Herz, Niculin J; Di Tullio, Giuseppe; Huynh, Tuong; Monfregola, Jlenia; Esposito, Alessandra; Cirillo, Carmine; Bajic, Aleksandar; Zahabiyon, Mahla; Curnock, Rachel; Polishchuk, Elena; Parkitny, Luke; Medina, Diego Luis; Pastore, Nunzia; Cullen, Peter J; Parenti, Giancarlo; De Matteis, Maria Antonietta; Grumati, Paolo; Ballabio, Andrea. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 14:1(2023), p. 3911. [10.1038/s41467-023-39643-7]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/930705
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