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Parkinson

Publications on Parkinson

Nature Communications (Jul 23, 2024) Mutant mice with rod-specific VPS35 deletion exhibit retinal α-synuclein pathology-associated degeneration

Fu C, Yang N, Chuang JZ, Nakajima N, Iraha S, Roy N, Wu Z, Jiang Z, Otsu W, Radu RA, Yang HH, Lee MP, Worgall TS, Xiong WC, Sung CH

DOI: 10.1038/s41467-024-50189-0 >>

Featured image for “Mutant mice with rod-specific VPS35 deletion exhibit retinal α-synuclein pathology-associated degeneration”

This study investigates the role of VPS35, a key component of the retromer complex, in Parkinson’s disease (PD) and its impact on vision. Researchers found that mice with VPS35-deficient rod cells in their retinas experienced synapse loss, visual deficits, and progressive degeneration. These changes were accompanied by the formation of Lewy body-like inclusions and phospho-α-synuclein aggregation. The study reveals a protein network involving VPS35 and HSC70, with VPS35 deficiency leading to accumulation of aggregates in late endosomes. Activated microglia were observed engulfing these aggregates, appearing as bright dots in fundus imaging. The OptoDrum with the ScotopicKit were used to measure visual acuity in mice under scotopic conditions.

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.