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ATAD3A oligomerization promotes neuropathology and cognitive deficits in Alzheimer’s disease models

Author

Listed:
  • Yuanyuan Zhao

    (Case Western Reserve University School of Medicine)

  • Di Hu

    (Case Western Reserve University School of Medicine)

  • Rihua Wang

    (Case Western Reserve University School of Medicine)

  • Xiaoyan Sun

    (Case Western Reserve University School of Medicine)

  • Philip Ropelewski

    (Case Western Reserve University School of Medicine)

  • Zita Hubler

    (Case Western Reserve University School of Medicine)

  • Kathleen Lundberg

    (Case Western Reserve University School of Medicine)

  • Quanqiu Wang

    (Case Western Reserve University School of Medicine)

  • Drew J. Adams

    (Case Western Reserve University School of Medicine)

  • Rong Xu

    (Case Western Reserve University School of Medicine)

  • Xin Qi

    (Case Western Reserve University School of Medicine)

Abstract

Predisposition to Alzheimer’s disease (AD) may arise from lipid metabolism perturbation, however, the underlying mechanism remains elusive. Here, we identify ATPase family AAA-domain containing protein 3A (ATAD3A), a mitochondrial AAA-ATPase, as a molecular switch that links cholesterol metabolism impairment to AD phenotypes. In neuronal models of AD, the 5XFAD mouse model and post-mortem AD brains, ATAD3A is oligomerized and accumulated at the mitochondria-associated ER membranes (MAMs), where it induces cholesterol accumulation by inhibiting gene expression of CYP46A1, an enzyme governing brain cholesterol clearance. ATAD3A and CYP46A1 cooperate to promote APP processing and synaptic loss. Suppressing ATAD3A oligomerization by heterozygous ATAD3A knockout or pharmacological inhibition with DA1 restores neuronal CYP46A1 levels, normalizes brain cholesterol turnover and MAM integrity, suppresses APP processing and synaptic loss, and consequently reduces AD neuropathology and cognitive deficits in AD transgenic mice. These findings reveal a role for ATAD3A oligomerization in AD pathogenesis and suggest ATAD3A as a potential therapeutic target for AD.

Suggested Citation

  • Yuanyuan Zhao & Di Hu & Rihua Wang & Xiaoyan Sun & Philip Ropelewski & Zita Hubler & Kathleen Lundberg & Quanqiu Wang & Drew J. Adams & Rong Xu & Xin Qi, 2022. "ATAD3A oligomerization promotes neuropathology and cognitive deficits in Alzheimer’s disease models," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28769-9
    DOI: 10.1038/s41467-022-28769-9
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    References listed on IDEAS

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    1. Natasha Chandiramani & Xianhong Wang & Marta Margeta, 2011. "Molecular Basis for Vulnerability to Mitochondrial and Oxidative Stress in a Neuroendocrine CRI-G1 Cell Line," PLOS ONE, Public Library of Science, vol. 6(1), pages 1-18, January.
    2. Yuanyuan Zhao & Xiaoyan Sun & Di Hu & Domenick A. Prosdocimo & Charles Hoppel & Mukesh K. Jain & Rajesh Ramachandran & Xin Qi, 2019. "ATAD3A oligomerization causes neurodegeneration by coupling mitochondrial fragmentation and bioenergetics defects," Nature Communications, Nature, vol. 10(1), pages 1-20, December.
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