Retinal α-synuclein deposits in Parkinson’s disease patients and animal models

Abstract

Despite decades of research, accurate diagnosis of Parkinson's disease remains a challenge, and disease-modifying treatments are still lacking. Research into the early (presymptomatic) stages of Parkinson's disease and the discovery of novel biomarkers is of utmost importance to reduce this burden and to come to a more accurate diagnosis at the very onset of the disease. Many have speculated that non-motor symptoms could provide a breakthrough in the quest for early biomarkers of Parkinson's disease, including the visual disturbances and retinal abnormalities that are seen in the majority of Parkinson's disease patients. An expanding number of clinical studies have investigated the use of in vivo assessments of retinal structure, electrophysiological function, and vision-driven tasks as novel means for identifying patients at risk that need further neurological examination and for longitudinal follow-up of disease progression in Parkinson's disease patients. Often, the results of these studies have been interpreted in relation to α-synuclein deposits and dopamine deficiency in the retina, mirroring the defining pathological features of Parkinson's disease in the brain. To better understand the visual defects seen in Parkinson's disease patients and to propel the use of retinal changes as biomarkers for Parkinson's disease, however, more conclusive neuropathological evidence for the presence of retinal α-synuclein aggregates, and its relation to the cerebral α-synuclein burden, is urgently needed. This review provides a comprehensive and critical overview of the research conducted to unveil α-synuclein aggregates in the retina of Parkinson's disease patients and animal models, and thereby aims to aid the ongoing discussion about the potential use of the retinal changes and/or visual symptoms as biomarkers for Parkinson's disease.

Dopaminergic Retinal Cell Loss and Visual Dysfunction in Parkinson Disease

“…Nevertheless, in contrast with what happens in the brain, previous studies had not found phosphorylated α-synuclein deposits within retinal dopaminergic cells in patients suffering from PD. 2,3,61 We and others have always found scarce and sparse retinal phosphorylated α-synuclein deposits in the ganglion cell layer, and never within dopaminergic cells. This finding suggests that dopaminergic cell death in the retina is independent of a self-accumulation of phosphorylated α-synuclein or that the levels of phosphorylated α-synuclein are low and the techniques used are not able to detect it.…”

“…Among them, the retina has been recently proposed to reflect the PD brain pathology: phosphorylated α-synuclein deposits, similar to Lewy bodies, have been found in the retina of PD patients, whose density correlated with disease severity. 2,3 In addition, PD patients present several visual symptoms, such as reduced amplitudes in b-waves and oscillatory potentials on electroretinograms (ERGs), reduced visual evoked potentials, inner retinal layer thinning by optical coherence tomography (OCT), 4 impaired motion perception, contrast sensitivity, and color discrimination, [5][6][7][8] circadian rhythm dysfunction, 9,10 and melanopsin-containing retinal ganglion cell (mRGC) degeneration. 11 Considering the described similarities between the neurodegenerative process in the retina and brain, it is natural to wonder whether the dopaminergic cells in the retina are involved in the disease as they are in the brain.…”

Retinal Thickness and Microvascular Pattern in Early Parkinson's Disease

“…αSYN, as native monomeric inclusions, has been found in the retina of HCs, where it could play a role into neurotransmission, synaptic plasticity, and vesicle trafficking (39). Instead, phosphor-αSYN has been found only in PD patients' retina, just within the somata and neurites of RNFL, GCL, and IPL (40,41). Thus, it has been supposed that visual impairment reported in PD may be due to dopamine depletion and α-synuclein accumulation in the retinal layers.…”

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

“…Moreover, accumulating experimental evidence suggests that pathological α-Syn aggregates are present in the retina and/or visual system of PD patients and of PD animal models. In addition, phosphorylated α-Syn accumulates in the retina as well as in the brain also at early stages, preceding the appearance of clinical signs of parkinsonism or dementia (Guo et al, 2018;Ortuno-Lizaran et al, 2018;Veys et al, 2019). Visual symptoms are probably the least invalidating symptoms in PD and DLB but they are being seriously considered as significant disease biomarkers.…”