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

Author

Listed:
  • Alessia Calcagni’

    (Baylor College of Medicine
    Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital)

  • Leopoldo Staiano

    (Telethon Institute of Genetics and Medicine (TIGEM)
    National Research Council (CNR))

  • Nicolina Zampelli

    (Telethon Institute of Genetics and Medicine (TIGEM))

  • Nadia Minopoli

    (Telethon Institute of Genetics and Medicine (TIGEM)
    Federico II University)

  • Niculin J. Herz

    (Baylor College of Medicine
    Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital)

  • Giuseppe Tullio

    (Telethon Institute of Genetics and Medicine (TIGEM))

  • Tuong Huynh

    (Baylor College of Medicine
    Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital)

  • Jlenia Monfregola

    (Telethon Institute of Genetics and Medicine (TIGEM))

  • Alessandra Esposito

    (Telethon Institute of Genetics and Medicine (TIGEM)
    Federico II University)

  • Carmine Cirillo

    (Telethon Institute of Genetics and Medicine (TIGEM))

  • Aleksandar Bajic

    (Baylor College of Medicine
    Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital)

  • Mahla Zahabiyon

    (Baylor College of Medicine
    Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital)

  • Rachel Curnock

    (University of Bristol)

  • Elena Polishchuk

    (Telethon Institute of Genetics and Medicine (TIGEM))

  • Luke Parkitny

    (Baylor College of Medicine
    Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital)

  • Diego Luis Medina

    (Telethon Institute of Genetics and Medicine (TIGEM)
    Federico II University)

  • Nunzia Pastore

    (Telethon Institute of Genetics and Medicine (TIGEM)
    Federico II University)

  • Peter J. Cullen

    (University of Bristol)

  • Giancarlo Parenti

    (Telethon Institute of Genetics and Medicine (TIGEM)
    Federico II University)

  • Maria Antonietta Matteis

    (Telethon Institute of Genetics and Medicine (TIGEM)
    Federico II University)

  • Paolo Grumati

    (Telethon Institute of Genetics and Medicine (TIGEM)
    Federico II University)

  • Andrea Ballabio

    (Baylor College of Medicine
    Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital
    Telethon Institute of Genetics and Medicine (TIGEM)
    Federico II University)

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.

Suggested Citation

  • Alessia Calcagni’ & Leopoldo Staiano & Nicolina Zampelli & Nadia Minopoli & Niculin J. Herz & Giuseppe Tullio & Tuong Huynh & Jlenia Monfregola & Alessandra Esposito & Carmine Cirillo & Aleksandar Baj, 2023. "Loss of the batten disease protein CLN3 leads to mis-trafficking of M6PR and defective autophagic-lysosomal reformation," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39643-7
    DOI: 10.1038/s41467-023-39643-7
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    1. Nouf N. Laqtom & Wentao Dong & Uche N. Medoh & Andrew L. Cangelosi & Vimisha Dharamdasani & Sze Ham Chan & Tenzin Kunchok & Caroline A. Lewis & Ivonne Heinze & Rachel Tang & Christian Grimm & An N. Da, 2022. "CLN3 is required for the clearance of glycerophosphodiesters from lysosomes," Nature, Nature, vol. 609(7929), pages 1005-1011, September.
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    1. Cheng Fu & Nan Yang & Jen-Zen Chuang & Nobuyuki Nakajima & Satoshi Iraha & Neeta Roy & Zhenquan Wu & Zhichun Jiang & Wataru Otsu & Roxana A. Radu & Howard Hua Yang & Maxwell Ping Lee & Tilla S. Worgal, 2024. "Mutant mice with rod-specific VPS35 deletion exhibit retinal α-synuclein pathology-associated degeneration," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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