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

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. Worgall, Wen-Cheng Xiong and Ching-Hwa Sung ()
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Cheng Fu: Weill Cornell Medicine
Nan Yang: Weill Cornell Medicine
Jen-Zen Chuang: Weill Cornell Medicine
Nobuyuki Nakajima: Weill Cornell Medicine
Satoshi Iraha: Weill Cornell Medicine
Neeta Roy: Weill Cornell Medicine
Zhenquan Wu: Weill Cornell Medicine
Zhichun Jiang: David Geffen School of Medicine at UCLA
Wataru Otsu: Weill Cornell Medicine
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

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50189-0

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