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

Abstract

Parkinson's disease (PD) is characterized by motor dysfunctions including bradykinesia, tremor at rest and motor instability. These symptoms are associated with the progressive degeneration of dopaminergic neurons originating in the substantia nigra pars compacta and projecting to the corpus striatum, and by accumulation of cytoplasmic inclusions mainly consisting of aggregated alpha-synuclein, called Lewy bodies. PD is a complex, multifactorial disorder and its pathogenesis involves multiple pathways and mechanisms such as α-synuclein proteostasis, mitochondrial function, oxidative stress, calcium homeostasis, axonal transport, and neuroinflammation. Motor symptoms manifest when there is already an extensive dopamine denervation. There is therefore an urgent need for early biomarkers to apply disease-modifying therapeutic strategies. Visual defects and retinal abnormalities, including decreased visual acuity, abnormal spatial contrast sensitivity, color vision defects, or deficits in more complex visual tasks are present in the majority of PD patients. They are being considered for early diagnosis together with retinal imaging techniques are being considered as non-invasive biomarkers for PD. Dopaminergic cells can be found in the retina in a subpopulation of amacrine cells; however, the molecular mechanisms leading to visual deficits observed in PD patients are still largely unknown. This review provides a comprehensive analysis of the retinal abnormalities observed in PD patients and animal models and of the molecular mechanisms underlying neurodegeneration in parkinsonian eyes. We will review the role of α-synuclein aggregates in the retina pathology and/or in the onset of visual symptoms in PD suggesting that α-synuclein aggregates are harmful for the retina as well as for the brain. Moreover, we will summarize experimental evidence suggesting that the optic nerve pathology observed in PD resembles that seen in mitochondrial optic neuropathies highlighting the possible involvement of mitochondrial abnormalities in the development of PD visual defects. We finally propose that the eye may be considered as a complementary experimental model to identify possible novel disease' pathways or to test novel therapeutic approaches for PD.

Keywords: Parkinson’ disease; alpha-synuclein; dopamine; mitochondria; optic neuropathies; parkinsonism; retina; visual dysfunctions.

FIGURE 1

Schematic representation of the retina with cell types expressing specific dopamine receptors. Dopamine receptors D1R, D4R, and D2 autoreceptors localized on various cell types, are indicated light blue, light green and fuchsia, respectively. DACs stratify in the IPL and send axons like dendritic projections to OPL and to IPL.ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, canglion cell layer; DAC, dopaminergic amacrine cell.

FIGURE 2

Anatomical and functional alterations in the retina of a PD patient. (A) Retinal section from a PD patient stained for Phospho-α-Synuclein shows the presence of aggregates both in neuronal axons (arrowheads) and soma (arrow). (B) Comparison of the scotopic a-wave, photopic b-wave and the Oscillatory Potential recorded from a control and a PD patient. Note the reduction in amplitude. Modified from Veys et al. (2019) (A) and Nowacka et al. (2015) (B) under terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).

FIGURE 3

(A) Representative immunofluorescence showing retinal sections of rAAV-hu-α-syn injected mice and rAAV-GFP mice stained with antibody anti-hu-α-syn (A-SYN) (red) and antibody anti-phospho α-syn (P-ASYN). (B) Representative images of the retina whole mount anti-TH immunofluorescence on Not injected, rAAV-GFP- and rAAV-hu-α-syn-injected mice at 2 months post-injection. (C) Number of TH-positive cells. N ≥ 5. Data represent mean ± SEM. ###p < 0.0001 vs. rAAV-GFP. Significance was calculated by one-way ANOVA. Modified from Marrocco et al. (2020) under terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).