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

Alessia Calcagni’ (), Leopoldo Staiano, Nicolina Zampelli, Nadia Minopoli, Niculin J. Herz, Giuseppe Tullio, Tuong Huynh, Jlenia Monfregola, Alessandra Esposito, Carmine Cirillo, Aleksandar Bajic, Mahla Zahabiyon, Rachel Curnock, Elena Polishchuk, Luke Parkitny, Diego Luis Medina, Nunzia Pastore, Peter J. Cullen, Giancarlo Parenti, Maria Antonietta Matteis, Paolo Grumati and Andrea Ballabio ()
Additional contact information
Alessia Calcagni’: Baylor College of Medicine
Leopoldo Staiano: Telethon Institute of Genetics and Medicine (TIGEM)
Nicolina Zampelli: Telethon Institute of Genetics and Medicine (TIGEM)
Nadia Minopoli: Telethon Institute of Genetics and Medicine (TIGEM)
Niculin J. Herz: Baylor College of Medicine
Giuseppe Tullio: Telethon Institute of Genetics and Medicine (TIGEM)
Tuong Huynh: Baylor College of Medicine
Jlenia Monfregola: Telethon Institute of Genetics and Medicine (TIGEM)
Alessandra Esposito: Telethon Institute of Genetics and Medicine (TIGEM)
Carmine Cirillo: Telethon Institute of Genetics and Medicine (TIGEM)
Aleksandar Bajic: Baylor College of Medicine
Mahla Zahabiyon: Baylor College of Medicine
Rachel Curnock: University of Bristol
Elena Polishchuk: Telethon Institute of Genetics and Medicine (TIGEM)
Luke Parkitny: Baylor College of Medicine
Diego Luis Medina: Telethon Institute of Genetics and Medicine (TIGEM)
Nunzia Pastore: Telethon Institute of Genetics and Medicine (TIGEM)
Peter J. Cullen: University of Bristol
Giancarlo Parenti: Telethon Institute of Genetics and Medicine (TIGEM)
Maria Antonietta Matteis: Telethon Institute of Genetics and Medicine (TIGEM)
Paolo Grumati: Telethon Institute of Genetics and Medicine (TIGEM)
Andrea Ballabio: Baylor College of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39643-7

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