α-synuclein overexpression in the retina leads to vision impairment and degeneration of dopaminergic amacrine cells

Abstract

the presence of α-synuclein aggregates in the retina of parkinson's disease patients has been associated with vision impairment. In this study we sought to determine the effects of α-synuclein overexpression on the survival and function of dopaminergic amacrine cells (DACs) in the retina. Adult mice were intravitreally injected with an adeno-associated viral (AAV) vector to overexpress human wild-type α-synuclein in the inner retina. Before and after systemic injections of levodopa (L-DOPA), retinal responses and visual acuity-driven behavior were measured by electroretinography (ERG) and a water maze task, respectively. Amacrine cells and ganglion cells were counted at different time points after the injection. α-synuclein overexpression led to an early loss of DACs associated with a decrease of light-adapted ERG responses and visual acuity that could be rescued by systemic injections of L-DOPA. The data show that α-synuclein overexpression affects dopamine neurons in the retina. The approach provides a novel accessible method to model the underlying mechanisms implicated in the pathogenesis of synucleinopathies and for testing novel treatments.

Presynaptic accumulation of α-synuclein causes synaptopathy and progressive neurodegeneration

“…Indeed, quantification of the SSVEP (Afsari et al, 2014;Petridi et al, 2020) revealed altered synaptic efficacy caused by α-syn accumulation in TH>WT-α-syn-EGFP flies. These observations in Drosophila are in line with a recent study in rodents which showed that overexpression of α-syn caused impairment in the electroretinogram and loss of TH positive amacrine cells in the retina (Marrocco et al, 2020).…”

Dopamine, Alpha-Synuclein, and Mitochondrial Dysfunctions in Parkinsonian Eyes

“…As for (Thy-1)-hu-A30P-α-Syn transgenic mice and PD patients' retinas, pSer129α-Syn accumulation were found in cells bodies of GCL and INL, and in the IPL neurites ( Figure 3A). These results were mirrored by an early loss in the number of TH + amacrine cells (Figures 3B,C) that precede in time the loss of the RGCs (Marrocco et al, 2020). Notably this study demonstrated for the first time that α-Syn overexpression in the retina leads to neurodegeneration of DA amacrine cells, causing retinal-specific defects and consequent visual impairment that resemble the human PD phenotype (Marrocco et al, 2020).…”

“…These results were mirrored by an early loss in the number of TH + amacrine cells (Figures 3B,C) that precede in time the loss of the RGCs (Marrocco et al, 2020). Notably this study demonstrated for the first time that α-Syn overexpression in the retina leads to neurodegeneration of DA amacrine cells, causing retinal-specific defects and consequent visual impairment that resemble the human PD phenotype (Marrocco et al, 2020). These findings is even more interesting in light of very recent evidence reporting a specific reduction of the DAC number as well as of the number of their synaptic contacts with AII amacrine cells and melanopsin cells reported in the retina of PD patients (Ortuno-Lizaran et al, 2020).…”

“…Abnormal PERG responses of the RGC have been observed in monkeys intravitreally injected with 6-OHDA (Bodis-Wollner and Tzelepi, 1998). Finally, intravitreal administration of 6-OHDA in mice resulted in a significant decrease of DACs and impairment of visual-acuity, which was rescued by L-DOPA (Marrocco et al, 2020).…”

“…Recently, intravitreal injection of adeno-associated viral (AAV) vectors over-expressing the wt human α-Syn (hu-α-Syn) has been used to evaluate the effects of α-Syn overexpression in the mouse retina (Marrocco et al, 2020). AAVhu-α-Syn injected mice displayed a time-dependent decrease of the amplitude of light-adapted responses while those elicited in dark-adapted conditions were not affected.…”