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NPC1-dependent alterations in KV2.1–CaV1.2 nanodomains drive neuronal death in models of Niemann-Pick Type C disease

Author

Listed:
  • Maria Casas

    (University of California)

  • Karl D. Murray

    (University of California
    University of California)

  • Keiko Hino

    (University of California)

  • Nicholas C. Vierra

    (University of California)

  • Sergi Simó

    (University of California)

  • James S. Trimmer

    (University of California)

  • Rose E. Dixon

    (University of California)

  • Eamonn J. Dickson

    (University of California)

Abstract

Lysosomes communicate through cholesterol transfer at endoplasmic reticulum (ER) contact sites. At these sites, the Niemann Pick C1 cholesterol transporter (NPC1) facilitates the removal of cholesterol from lysosomes, which is then transferred to the ER for distribution to other cell membranes. Mutations in NPC1 result in cholesterol buildup within lysosomes, leading to Niemann-Pick Type C (NPC) disease, a progressive and fatal neurodegenerative disorder. The molecular mechanisms connecting NPC1 loss to NPC-associated neuropathology remain unknown. Here we show both in vitro and in an animal model of NPC disease that the loss of NPC1 function alters the distribution and activity of voltage-gated calcium channels (CaV). Underlying alterations in calcium channel localization and function are KV2.1 channels whose interactions drive calcium channel clustering to enhance calcium entry and fuel neurotoxic elevations in mitochondrial calcium. Targeted disruption of KV2–CaV interactions rescues aberrant CaV1.2 clustering, elevated mitochondrial calcium, and neurotoxicity in vitro. Our findings provide evidence that NPC is a nanostructural ion channel clustering disease, characterized by altered distribution and activity of ion channels at membrane contacts, which contribute to neurodegeneration.

Suggested Citation

  • Maria Casas & Karl D. Murray & Keiko Hino & Nicholas C. Vierra & Sergi Simó & James S. Trimmer & Rose E. Dixon & Eamonn J. Dickson, 2023. "NPC1-dependent alterations in KV2.1–CaV1.2 nanodomains drive neuronal death in models of Niemann-Pick Type C disease," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39937-w
    DOI: 10.1038/s41467-023-39937-w
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    References listed on IDEAS

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    1. Francesca Vallese & Cristina Catoni & Domenico Cieri & Lucia Barazzuol & Omar Ramirez & Valentina Calore & Massimo Bonora & Flavia Giamogante & Paolo Pinton & Marisa Brini & Tito Calì, 2020. "An expanded palette of improved SPLICS reporters detects multiple organelle contacts in vitro and in vivo," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    2. Nagendra Babu Thillaiappan & Alap P. Chavda & Stephen C. Tovey & David L. Prole & Colin W. Taylor, 2017. "Ca2+ signals initiate at immobile IP3 receptors adjacent to ER-plasma membrane junctions," Nature Communications, Nature, vol. 8(1), pages 1-16, December.
    3. Frederick R. Maxfield & Ira Tabas, 2005. "Role of cholesterol and lipid organization in disease," Nature, Nature, vol. 438(7068), pages 612-621, December.
    4. Margareta Nikolic & Margaret M. Chou & Wange Lu & Bruce J. Mayer & Li-Huei Tsai, 1998. "The p35/Cdk5 kinase is a neuron-specific Rac effector that inhibits Pak1 activity," Nature, Nature, vol. 395(6698), pages 194-198, September.
    5. Mouhannad Malek & Anna M. Wawrzyniak & Peter Koch & Christian Lüchtenborg & Manuel Hessenberger & Timo Sachsenheimer & Wonyul Jang & Britta Brügger & Volker Haucke, 2021. "Inositol triphosphate-triggered calcium release blocks lipid exchange at endoplasmic reticulum-Golgi contact sites," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    6. Maria Calvo-Rodriguez & Steven S. Hou & Austin C. Snyder & Elizabeth K. Kharitonova & Alyssa N. Russ & Sudeshna Das & Zhanyun Fan & Alona Muzikansky & Monica Garcia-Alloza & Alberto Serrano-Pozo & Elo, 2020. "Increased mitochondrial calcium levels associated with neuronal death in a mouse model of Alzheimer’s disease," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
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