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Mutant mice with rod-specific VPS35 deletion exhibit retinal α-synuclein pathology-associated degeneration

Author

Listed:
  • Cheng Fu

    (Weill Cornell Medicine)

  • Nan Yang

    (Weill Cornell Medicine)

  • Jen-Zen Chuang

    (Weill Cornell Medicine)

  • Nobuyuki Nakajima

    (Weill Cornell Medicine
    Tokai University School of Medicipne)

  • Satoshi Iraha

    (Weill Cornell Medicine
    Faculty of Life Sciences, Kumamoto University; Department of Ophthalmology, National Sanatorium Kikuchi Keifuen)

  • Neeta Roy

    (Weill Cornell Medicine)

  • Zhenquan Wu

    (Weill Cornell Medicine)

  • Zhichun Jiang

    (David Geffen School of Medicine at UCLA)

  • Wataru Otsu

    (Weill Cornell Medicine
    Gifu Pharmaceutical University)

  • Roxana A. Radu

    (David Geffen School of Medicine at UCLA)

  • Howard Hua Yang

    (National Cancer Institute, National Institutes of Health)

  • Maxwell Ping Lee

    (National Cancer Institute, National Institutes of Health)

  • Tilla S. Worgall

    (Columbia University Medical Center)

  • Wen-Cheng Xiong

    (Case Western Reserve University)

  • Ching-Hwa Sung

    (Weill Cornell Medicine
    Weill Cornell Medicine)

Abstract

Vacuolar protein sorting 35 (VPS35), the core component of the retromer complex which regulates endosomal trafficking, is genetically linked with Parkinson’s disease (PD). Impaired vision is a common non-motor manifestation of PD. Here, we show mouse retinas with VPS35-deficient rods exhibit synapse loss and visual deficit, followed by progressive degeneration concomitant with the emergence of Lewy body-like inclusions and phospho-α-synuclein (P-αSyn) aggregation. Ultrastructural analyses reveal VPS35-deficient rods accumulate aggregates in late endosomes, deposited as lipofuscins bound to P-αSyn. Mechanistically, we uncover a protein network of VPS35 and its interaction with HSC70. VPS35 deficiency promotes sequestration of HSC70 and P-αSyn aggregation in late endosomes. Microglia which engulf lipofuscins and P-αSyn aggregates are activated, displaying autofluorescence, observed as bright dots in fundus imaging of live animals, coinciding with pathology onset and progression. The Rod∆Vps35 mouse line is a valuable tool for further mechanistic investigation of αSyn lesions and retinal degenerative diseases.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50189-0
    DOI: 10.1038/s41467-024-50189-0
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    References listed on IDEAS

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