IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-42822-1.html
   My bibliography  Save this article

Integrative analysis reveals a conserved role for the amyloid precursor protein in proteostasis during aging

Author

Listed:
  • Vanitha Nithianandam

    (Brigham and Women’s Hospital, Harvard Medical School
    Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network)

  • Hassan Bukhari

    (Brigham and Women’s Hospital, Harvard Medical School
    Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network)

  • Matthew J. Leventhal

    (Massachusetts Institute of Technology
    MIT Ph.D. Program in Computational and Systems Biology)

  • Rachel A. Battaglia

    (Brigham and Women’s Hospital, Harvard Medical School
    Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network)

  • Xianjun Dong

    (Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network
    Genomics and Bioinformatics Hub, Brigham and Women’s Hospital)

  • Ernest Fraenkel

    (Massachusetts Institute of Technology)

  • Mel B. Feany

    (Brigham and Women’s Hospital, Harvard Medical School
    Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network)

Abstract

Aβ peptides derived from the amyloid precursor protein (APP) have been strongly implicated in the pathogenesis of Alzheimer’s disease. However, the normal function of APP and the importance of that role in neurodegenerative disease is less clear. We recover the Drosophila ortholog of APP, Appl, in an unbiased forward genetic screen for neurodegeneration mutants. We perform comprehensive single cell transcriptional and proteomic studies of Appl mutant flies to investigate Appl function in the aging brain. We find an unexpected role for Appl in control of multiple cellular pathways, including translation, mitochondrial function, nucleic acid and lipid metabolism, cellular signaling and proteostasis. We mechanistically define a role for Appl in regulating autophagy through TGFβ signaling and document the broader relevance of our findings using mouse genetic, human iPSC and in vivo tauopathy models. Our results demonstrate a conserved role for APP in controlling age-dependent proteostasis with plausible relevance to Alzheimer’s disease.

Suggested Citation

  • Vanitha Nithianandam & Hassan Bukhari & Matthew J. Leventhal & Rachel A. Battaglia & Xianjun Dong & Ernest Fraenkel & Mel B. Feany, 2023. "Integrative analysis reveals a conserved role for the amyloid precursor protein in proteostasis during aging," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42822-1
    DOI: 10.1038/s41467-023-42822-1
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-42822-1
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-42822-1?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. Ira E. Clark & Mark W. Dodson & Changan Jiang & Joseph H. Cao & Jun R. Huh & Jae Hong Seol & Soon Ji Yoo & Bruce A. Hay & Ming Guo, 2006. "Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin," Nature, Nature, vol. 441(7097), pages 1162-1166, June.
    2. Caroline Mauvezin & Péter Nagy & Gábor Juhász & Thomas P. Neufeld, 2015. "Autophagosome–lysosome fusion is independent of V-ATPase-mediated acidification," Nature Communications, Nature, vol. 6(1), pages 1-14, November.
    3. Jeehye Park & Sung Bae Lee & Sungkyu Lee & Yongsung Kim & Saera Song & Sunhong Kim & Eunkyung Bae & Jaeseob Kim & Minho Shong & Jin-Man Kim & Jongkyeong Chung, 2006. "Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin," Nature, Nature, vol. 441(7097), pages 1157-1161, June.
    4. Thorlakur Jonsson & Jasvinder K. Atwal & Stacy Steinberg & Jon Snaedal & Palmi V. Jonsson & Sigurbjorn Bjornsson & Hreinn Stefansson & Patrick Sulem & Daniel Gudbjartsson & Janice Maloney & Kwame Hoyt, 2012. "A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline," Nature, Nature, vol. 488(7409), pages 96-99, August.
    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. Yunpeng Huang & Zhihui Wan & Yinglu Tang & Junxuan Xu & Bretton Laboret & Sree Nallamothu & Chenyu Yang & Boxiang Liu & Rongze Olivia Lu & Bingwei Lu & Juan Feng & Jing Cao & Susan Hayflick & Zhihao W, 2022. "Pantothenate kinase 2 interacts with PINK1 to regulate mitochondrial quality control via acetyl-CoA metabolism," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Huan Yang & Caroline Sibilla & Raymond Liu & Jina Yun & Bruce A. Hay & Craig Blackstone & David C. Chan & Robert J. Harvey & Ming Guo, 2022. "Clueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    3. Federico Miozzo & Eva P. Valencia-Alarcón & Luca Stickley & Michaëla Majcin Dorcikova & Francesco Petrelli & Damla Tas & Nicolas Loncle & Irina Nikonenko & Peter Bou Dib & Emi Nagoshi, 2022. "Maintenance of mitochondrial integrity in midbrain dopaminergic neurons governed by a conserved developmental transcription factor," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    4. Jenny Zhe Liao & Hyung-lok Chung & Claire Shih & Kenneth Kin Lam Wong & Debdeep Dutta & Zelha Nil & Catherine Grace Burns & Oguz Kanca & Ye-Jin Park & Zhongyuan Zuo & Paul C. Marcogliese & Katherine S, 2024. "Cdk8/CDK19 promotes mitochondrial fission through Drp1 phosphorylation and can phenotypically suppress pink1 deficiency in Drosophila," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    5. Zhang, Yongxin & Dong, Mingyan & Li, Bai-Lian & Sun, Gui-Quan, 2024. "Analysis for a model incorporating γ−secretase inhibitor to explore the mechanism of ‘Amyloid-β rise’," Chaos, Solitons & Fractals, Elsevier, vol. 183(C).
    6. Su Jin Ham & Heesuk Yoo & Daihn Woo & Da Hyun Lee & Kyu-Sang Park & Jongkyeong Chung, 2023. "PINK1 and Parkin regulate IP3R-mediated ER calcium release," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    7. Robin Caire & Estelle Audoux & Mireille Thomas & Elisa Dalix & Aurélien Peyron & Killian Rodriguez & Nicola Pordone & Johann Guillemot & Yann Dickerscheit & Hubert Marotte & François Vandenesch & Fréd, 2022. "YAP promotes cell-autonomous immune responses to tackle intracellular Staphylococcus aureus in vitro," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    8. Marc Thilo Figge & Andreas S Reichert & Michael Meyer-Hermann & Heinz D Osiewacz, 2012. "Deceleration of Fusion–Fission Cycles Improves Mitochondrial Quality Control during Aging," PLOS Computational Biology, Public Library of Science, vol. 8(6), pages 1-18, June.
    9. Kimberly C. Paul & Richard C. Krolewski & Edinson Lucumi Moreno & Jack Blank & Kristina M. Holton & Tim Ahfeldt & Melissa Furlong & Yu Yu & Myles Cockburn & Laura K. Thompson & Alexander Kreymerman & , 2023. "A pesticide and iPSC dopaminergic neuron screen identifies and classifies Parkinson-relevant pesticides," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    10. Joshua J. Rennick & Cameron J. Nowell & Colin W. Pouton & Angus P. R. Johnston, 2022. "Resolving subcellular pH with a quantitative fluorescent lifetime biosensor," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    11. Keiji Kajiwara & Hiroshi Osaki & Steffen Greßies & Keiko Kuwata & Ju Hyun Kim & Tobias Gensch & Yoshikatsu Sato & Frank Glorius & Shigehiro Yamaguchi & Masayasu Taki, 2022. "A negative-solvatochromic fluorescent probe for visualizing intracellular distributions of fatty acid metabolites," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    12. Snaedis Kristmundsdottir & Hakon Jonsson & Marteinn T. Hardarson & Gunnar Palsson & Doruk Beyter & Hannes P. Eggertsson & Arnaldur Gylfason & Gardar Sveinbjornsson & Guillaume Holley & Olafur A. Stefa, 2023. "Sequence variants affecting the genome-wide rate of germline microsatellite mutations," Nature Communications, Nature, vol. 14(1), pages 1-12, 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_s41467-023-42822-1. 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.