2. Academic Validation
  3. Mutant mice with rod-specific VPS35 deletion exhibit retinal α-synuclein pathology-associated degeneration

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

  • Nat Commun. 2024 Jul 23;15(1):5970. doi: 10.1038/s41467-024-50189-0.
Cheng Fu # 1,  Nan Yang # 1,  Jen-Zen Chuang # 1,  Nobuyuki Nakajima # 1 2,  Satoshi Iraha # 1 3,  Neeta Roy 1,  Zhenquan Wu 1,  Zhichun Jiang 4,  Wataru Otsu 1 5,  Roxana A Radu 4,  Howard Hua Yang 6,  Maxwell Ping Lee 6,  Tilla S Worgall 7,  Wen-Cheng Xiong 8,  Ching-Hwa Sung 9 10
Affiliations

Affiliations

  • 1 Department of Ophthalmology, Margaret M. Dyson Vision Research Institute, Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA.
  • 2 Department of Urology, Tokai University School of Medicipne, Tokyo, Japan.
  • 3 Department of Ophthalmology, Faculty of Life Sciences, Kumamoto University; Department of Ophthalmology, National Sanatorium Kikuchi Keifuen, Kumamoto, Japan.
  • 4 UCLA Stein Eye Institute, and Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
  • 5 Department of Biomedical Research Laboratory, Gifu Pharmaceutical University, Gifu, Japan.
  • 6 The Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • 7 Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA.
  • 8 Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
  • 9 Department of Ophthalmology, Margaret M. Dyson Vision Research Institute, Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA. chsung@med.cornell.edu.
  • 10 Department of Cell and Developmental Biology, Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA. chsung@med.cornell.edu.
  • # Contributed equally.
PMID: 39043666 DOI: 10.1038/s41467-024-50189-0
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.

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