Loss of the Batten Disease Protein CLN3 Leads to Mis-Trafficking of M6PR and Defective Autophagic-Lysosomal Reformation

Authors

Alessia Calcagni'
Leopoldo Staiano
Nicolina Zampelli
Nadia Minopoli
Niculin J Herz
Giuseppe Di 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 De Matteis
Paolo Grumati
Andrea Ballabio

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

Published Open-Access

yes

Keywords

Humans, Membrane Glycoproteins, Neuronal Ceroid-Lipofuscinoses, Receptor, IGF Type 2, Proteomics, Molecular Chaperones, Lysosomes, Hydrolases, Autophagy, Mechanisms of disease, Lysosomes, Golgi

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.