1. Mutant mice with rod-specific VPS35 deletion exhibit retinal α-synuclein pathology-associated degeneration.
- Author
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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, and Sung, Ching-Hwa
- Subjects
Animals ,alpha-Synuclein ,Vesicular Transport Proteins ,Mice ,Retinal Degeneration ,Retinal Rod Photoreceptor Cells ,Endosomes ,Microglia ,Parkinson Disease ,Retina ,Mice ,Knockout ,Disease Models ,Animal ,Humans ,Synapses ,Male - 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.
- Published
- 2024