- Fu, Cheng;
- Yang, Nan;
- Chuang, Jen-Zen;
- Nakajima, Nobuyuki;
- Iraha, Satoshi;
- Roy, Neeta;
- Wu, Zhenquan;
- Jiang, Zhichun;
- Otsu, Wataru;
- Radu, Roxana A;
- Yang, Howard Hua;
- Lee, Maxwell Ping;
- Worgall, Tilla S;
- Xiong, Wen-Cheng;
- Sung, Ching-Hwa
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.