α‑Synuclein-Induced Increase in DOPA Decarboxylase-Expressing Cells in the Retina

Key findings: Intracranial mPFF injection induces α-synuclein propagation to the retina. DDC+ cell numbers increase in response to retinal α-synuclein accumulation, independently of TH+ cell loss..

Background: 

Parkinson’s disease (PD) is marked by the progressive loss of dopaminergic neurons in the substantia nigra, but growing evidence shows that pathology also affects the retina, making it a promising site for non‑invasive biomarker discovery. While tyrosine hydroxylase (TH) and dopa decarboxylase (DDC) together catalyze the two key steps of retinal dopamine synthesis, how these enzymes are altered in PD remains largely unknown.

Methods: 

Wild‑type mice were bilaterrally injected with α‑synuclein preformed fibrils (mPFFs) (n=7) or saline as controls (n=8). Retinas were collected and processed as either flat mounts or cross‑sections. Immunofluorescence staining was performed for phosphorylated α‑synuclein (pS129‑α‑syn), TH, and DDC to assess retinal α‑syn pathology and dopaminergic alterations.

Results: 

Immunofluorescent analysis of retinal tissue revealed increased accumulation of phosphorylated α‑synuclein, indicating propagation of pathological α‑synuclein to the retina. Concomitantly, we observed a significant increase in the number of DDC-positive cells, the enzyme catalyzing the final step in dopamine synthesis. In contrast, the number of TH-positive cells was not significantly altered.

Conclusion: 

Our findings indicate that intracranially injected α‑synuclein propagates to the retina and is associated with an increased population of DDC‑expressing cells, independent of dopaminergic cell loss. This suggests a potential compensatory retinal response to dopamine deficiency and highlights the retina as a promising site for studying PD‑related neurodegeneration.