Retina-to-brain spreading of α-synuclein after intravitreal injection of preformed fibrils

• Published in: Acta neuropathologica communications 2023-05, Vol.11 (1), p.83-20, Article 83
• Main Authors: Pérez-Acuña, Dayana, Rhee, Ka Hyun, Shin, Soo Jean, Ahn, Jeeyun, Lee, Jee-Young, Lee, Seung-Jae
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - metabolism; Animals; Antigens; Brain; Brain - pathology; Chromatography; Cloning; Graph representations; Humans; Hypotheses; Intravitreal Injections; Laboratories; Mice; Microscopy; Parkinson Disease - pathology; Parkinson's disease; Pathology; Protein aggregation; Proteins; Retina; Retina - pathology; Retinal degeneration; Spectrum analysis; α-synuclein
• ISSN: 2051-5960; 2051-5960
• DOI: 10.1186/s40478-023-01575-0

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the aggregation of misfolded α-synuclein and progressive spreading of the aggregates from a few discrete regions to wider brain regions. Although PD has been classically considered a movement disorder, a large body of clinical evidence has revealed the progressive occurrence of non-motor symptoms. Patients present visual symptoms in the initial stages of the disease, and accumulation of phospho-α-synuclein, dopaminergic neuronal loss, and retinal thinning has been observed in the retinas of PD patients. Based on such human data, we hypothesized that α-synuclein aggregation can initiate in the retina and spread to the brain through the visual pathway. Here, we demonstrate accumulation of α-synuclein in the retinas and brains of naive mice after intravitreal injection of α-synuclein preformed fibrils (PFFs). Histological analyses showed deposition of phospho-α-synuclein inclusions within the retina 2 months after injection, with increased oxidative stress leading to loss of retinal ganglion cells and dopaminergic dysfunction. In addition, we found accumulation of phospho-α-synuclein in cortical areas with accompanying neuroinflammation after 5 months. Collectively, our findings suggest that retinal synucleinopathy lesions initiated by intravitreal injection of α-synuclein PFFs spread to various brain regions through the visual pathway in mice.