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

Abstract

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.

Retinal ganglion cell type-specific expression of synuclein family members revealed by scRNA-sequencing

“…This observation suggests that α-Syn may not be highly susceptible to injury in the context of ONC. These findings contrast with the observed RGC loss and reduction in melanopsin-positive RGCs in PD models 59 and α-Syn overexpression in the retina 65 , 66 . This suggests that α-Syn positive RGCs may not be highly susceptible to traumatic injury but may be more vulnerable to chronic neurodegenerative processes associated with PD.…”

A topographical atlas of α-synuclein dosage and cell type-specific expression in adult mouse brain and peripheral organs

“…It was interesting to note that olfactory neurons (particularly TH+ , periglomerular cells) were highly enriched for αSyn whereas retinal ganglion cells and amacrine cells expressed very low levels of αSyn, which bordered on the lower limit of detection. This is consistent with recent findings that suggest the olfactory bulb is likely a richer source of seed-competent αSyn than the retina however contrary to a 2016 study that found wildtype αSyn does not colocalize with TH+ cells in the periglomerular olfactory bulb 62 – 66 . This discrepancy may be due to the presynaptic/cytosolic localization of αSyn in wildtype mice whereby TH+ neurons in the periglomerular region of the olfactory bulb can project outside this layer, making interpretation of wildtype αSyn localization difficult.…”

A new perspective on positive symptoms: expression of damage or self-defence mechanism of the brain?

“…Arguably, the CNS mainly needs to simulate inputs related to the most impaired sensory modality, whereas, for example the auditory side is less affected and, consequently, there is no need for hallucinations in order to speak. Indeed, alpha-synuclein has prion-like diffusion through the visual pathway and this could explain its preponderant and early involvement in LBD (since it is probably the starting point) and its later damage (according to Braak’s stages) in PD, justifying their different frequency and temporal sequence of visual hallucinations [ 15 ]. Furthermore, although LBD patients may also manifest parkinsonism due to dopaminergic alterations, this is not always present and is usually of lesser extent than in PD patients [ 14 ].…”