IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-39937-w.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-39937-w
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-39937-w?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    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. 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.
    4. 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.
    5. Frederick R. Maxfield & Ira Tabas, 2005. "Role of cholesterol and lipid organization in disease," Nature, Nature, vol. 438(7068), pages 612-621, 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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Flavia Giamogante & Lucia Barazzuol & Francesca Maiorca & Elena Poggio & Alessandra Esposito & Anna Masato & Gennaro Napolitano & Alessio Vagnoni & Tito Calì & Marisa Brini, 2024. "A SPLICS reporter reveals $${{{{{\boldsymbol{\alpha }}}}}}$$ α -synuclein regulation of lysosome-mitochondria contacts which affects TFEB nuclear translocation," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Katelyn C. Cook & Elene Tsopurashvili & Jason M. Needham & Sunnie R. Thompson & Ileana M. Cristea, 2022. "Restructured membrane contacts rewire organelles for human cytomegalovirus infection," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    3. Máté Katona & Ádám Bartók & Zuzana Nichtova & György Csordás & Elena Berezhnaya & David Weaver & Arijita Ghosh & Péter Várnai & David I. Yule & György Hajnóczky, 2022. "Capture at the ER-mitochondrial contacts licenses IP3 receptors to stimulate local Ca2+ transfer and oxidative metabolism," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    4. Abhishek Aich & Angela Boshnakovska & Steffen Witte & Tanja Gall & Kerstin Unthan-Fechner & Roya Yousefi & Arpita Chowdhury & Drishan Dahal & Aditi Methi & Svenja Kaufmann & Ivan Silbern & Jan Prochaz, 2024. "Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    5. Eunbyul Cho & Youngsik Woo & Yeongjun Suh & Bo Kyoung Suh & Soo Jeong Kim & Truong Thi My Nhung & Jin Yeong Yoo & Tran Diem Nghi & Su Been Lee & Dong Jin Mun & Sang Ki Park, 2023. "Ratiometric measurement of MAM Ca2+ dynamics using a modified CalfluxVTN," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    6. Vishal R. Patel & Arturo M. Salinas & Darong Qi & Shipra Gupta & David J. Sidote & Marcel P. Goldschen-Ohm, 2021. "Single-molecule imaging with cell-derived nanovesicles reveals early binding dynamics at a cyclic nucleotide-gated ion channel," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    7. Yuman Qin & Robin Cauwenbergh & Suman Pradhan & Rakesh Maiti & Philippe Franck & Shoubhik Das, 2023. "Straightforward synthesis of functionalized γ-Lactams using impure CO2 stream as the carbon source," Nature Communications, Nature, vol. 14(1), pages 1-9, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39937-w. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.