Dopaminergic Retinal Cell Loss and Visual Dysfunction in Parkinson Disease

Abstract

Objective: Considering the demonstrated implication of the retina in Parkinson disease (PD) pathology and the importance of dopaminergic cells in this tissue, we aimed to analyze the state of the dopaminergic amacrine cells and some of their main postsynaptic neurons in the retina of PD. Methods: Using immunohistochemistry and confocal microscopy, we evaluated morphology, number, and synaptic connections of dopaminergic cells and their postsynaptic cells, AII amacrine and melanopsin-containing retinal ganglion cells, in control and PD eyes from human donors. Results: In PD, dopaminergic amacrine cell number was reduced between 58% and 26% in different retinal regions, involving a decline in the number of synaptic contacts with AII amacrine cells (by 60%) and melanopsin cells (by 35%). Despite losing their main synaptic input, AII cells were not reduced in number, but they showed cellular alterations compromising their adequate function: (1) a loss of mitochondria inside their lobular appendages, which may indicate an energetic failure; and (2) a loss of connexin 36, suggesting alterations in the AII coupling and in visual signal transmission from the rod pathway. Interpretation: The dopaminergic system impairment and the affection of the rod pathway through the AII cells may explain and be partially responsible for the reduced contrast sensitivity or electroretinographic response described in PD. Also, dopamine reduction and the loss of synaptic contacts with melanopsin cells may contribute to the melanopsin retinal ganglion cell loss previously described and to the disturbances in circadian rhythm and sleep reported in PD patients. These data support the idea that the retina reproduces brain neurodegeneration and is highly involved in PD pathology.

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

“…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).…”

“…These finding point to a pivotal role of mitochondrial dysfunction in PD pathogenesis. Notably, in a recent study it was shown that AII cells were not reduced in PD patients, but they showed the loss of mitochondria in lobular appendages, which may indicate an energetic failure, and a loss of connexin 36, suggesting alterations in the AII coupling and in visual signal transmission from the rod pathway (Ortuno-Lizaran et al, 2020).…”

“…Although the specificity and predictive value of OCT and ERG changes in PD patients are still under debate, due to overlap with normal aging and other neurological and ophthalmological diseases, a better characterization of retinal dysfunctions during neurodegenerative diseases combined with imaging of protein aggregates may indeed represent a valuable approach for early diagnosis of PD. In this respect the presence of α-Syn deposits in the retina may have high potential for early diagnosis of PD (Veys et al, 2019;Ortuno-Lizaran et al, 2020). We thus believe that novel approaches integrating multiple biomarkers and employing novel technologies to increase diagnostic yield are needed and may be successfully applied in PD.…”

Multiple Pathways of LRRK2-G2019S/Rab10 Interaction in Dopaminergic Neurons

“…People with Parkinson's also show visual deficits including loss of dopaminergic neurons from the retina [35,36]. Aged THG2 flies also show strong retinal degeneration with vacuoles throughout the optic lobe [15].…”

Association of Visual Impairment with Risk for Future Parkinson’s Disease

“…Firstly, the 'bottom-up theory' postulated that impairment of the retinal dopaminergic system might explain visual abnormalities in PD 18 . Both animal and clinical studies had suggested that dopaminergic retinal cell loss was commonly seen in PD [19][20][21][22] . Further, aggregates of αsynuclein in the retina that mimiced the pathological process of PD, had been reported to cause neurodegeneration of the dopaminergic cells in the retina 23 .…”