Abstract
Abnormal α-synuclein (α-syn) accumulation in the CNS may underlie neuronal cell and synaptic dysfunction leading to motor and cognitive deficits in synucleinopathies including Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB). Multiple groups demonstrated α-syn accumulation in CNS accessory structures, including the eyes and olfactory terminals, as well as in peripheral organs of Parkinsonian patients. Retinal imaging studies of mice overexpressing fused α-syn::GFP were conducted to evaluate the presence and progression of retinal pathology in a PD/DLB transgenic mouse model. Bright-field image retinal maps and fluorescent images were acquired at 1-month intervals for 3 months. Retinal imaging revealed the accumulation of GFP-tagged α-syn in retinal ganglion cell layer and in the edges of arterial blood vessels in the transgenic mice. Double labeling studies confirmed that the α-syn::GFP-positive cells were retinal ganglion cells containing α-syn. Accumulation of α-syn persisted in the same cells and increased with age. Accumulation of α-syn::GFP was reduced by immunization with single chain antibodies against α-syn. In conclusion, longitudinal live imaging of the retina in the PDGF-α-syn::GFP mice might represent a useful, non-invasive tool to monitor the fate of α-syn accumulation in the CNS and to evaluate the therapeutic effects of compounds targeting α-syn.
Highlights
Abnormal accumulation of α-synuclein (α-syn) is hypothesized to underlie the dopaminergic and non-dopaminergic neuronal cell death and synaptic dysfunction leading to motor and cognitive symptoms in Parkinson’s disease (PD), PD dementia (PDD) and Dementia with Lewy Bodies (DLB)[1,2,3,4]
We evaluated a transgenic mouse model of PD/DLB for the presence and quality of α-syn deposits in the retina in an effort to develop a non-invasive live imaging assay that will allow longitudinal studies of α-syn accumulation in the retina as a way to evaluate the effects of aging, as well as therapeutical agents
Retinal imaging at four separate time points over a three-month period revealed accumulation of GFP-tagged α-syn in retinal ganglion cells, and this accumulation of α-syn persisted in the same cells over time and increased with age, supporting the notion that this method and model could be a useful tool to monitor in a non-invasive manner α-syn accumulation in the CNS in a non-invasive manner
Summary
Abnormal accumulation of α-synuclein (α-syn) is hypothesized to underlie the dopaminergic and non-dopaminergic neuronal cell death and synaptic dysfunction leading to motor and cognitive symptoms in Parkinson’s disease (PD), PD dementia (PDD) and Dementia with Lewy Bodies (DLB)[1,2,3,4]. Recent studies have shown the presence of α-syn deposits in the retina in PD patients[11,12] In this context, we evaluated a transgenic mouse model of PD/DLB for the presence and quality of α-syn deposits in the retina in an effort to develop a non-invasive live imaging assay that will allow longitudinal studies of α-syn accumulation in the retina as a way to evaluate the effects of aging, as well as therapeutical agents. We evaluated a transgenic mouse model of PD/DLB for the presence and quality of α-syn deposits in the retina in an effort to develop a non-invasive live imaging assay that will allow longitudinal studies of α-syn accumulation in the retina as a way to evaluate the effects of aging, as well as therapeutical agents For this purpose, we conducted retinal imaging studies in mice overexpressing fused α-syn-eGFP (α-syn::GFP) under the PDGF-beta promoter (PDNG78 line)[26]. Retinal imaging at four separate time points over a three-month period revealed accumulation of GFP-tagged α-syn in retinal ganglion cells, and this accumulation of α-syn persisted in the same cells over time and increased with age, supporting the notion that this method and model could be a useful tool to monitor in a non-invasive manner α-syn accumulation in the CNS in a non-invasive manner
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