Characterizing the Retinal Phenotype of the Thy1-h[A30P]α-syn Mouse Model of Parkinson’s Disease

Abstract

Despite decades of research, disease-modifying treatments of Parkinson’s disease (PD), the second most common neurodegenerative disease worldwide, remain out of reach. One of the reasons for this treatment gap is the incomplete understanding of how misfolded alpha-synuclein (α-syn) contributes to PD pathology. The retina, as an integral part of the central nervous system, recapitulates the PD disease processes that are typically seen in the brain, and retinal manifestations have emerged as prodromal symptoms of the disease. The timeline of PD manifestations in the visual system, however, is not fully elucidated and the underlying mechanisms are obscure. This highlights the need for new studies investigating retinal pathology, in order to propel its use as PD biomarker, and to develop validated research models to investigate PD pathogenesis. The present study pioneers in characterizing the retina of the Thy1-h[A30P]α-syn PD transgenic mouse model. We demonstrate widespread α-syn accumulation in the inner retina of these mice, of which a proportion is phosphorylated yet not aggregated. This α-syn expression coincides with inner retinal atrophy due to postsynaptic degeneration. We also reveal abnormal retinal electrophysiological responses. Absence of selective loss of melanopsin retinal ganglion cells or dopaminergic amacrine cells and inflammation indicates that the retinal manifestations in these transgenic mice diverge from their brain phenotype, and questions the specific cellular or molecular alterations that underlie retinal pathology in this PD mouse model. Nevertheless, the observed α-syn accumulation, synapse loss and functional deficits suggest that the Thy1-h[A30P]α-syn retina mimics some of the features of prodromal PD, and thus may provide a window to monitor and study the preclinical/prodromal stages of PD, PD-associated retinal disease processes, as well as aid in retinal biomarker discovery and validation.

Expression of α‐Synuclein in the mouse retina is confined to inhibitory presynaptic elements

“…First, it has been proposed that cell bodies expressing α‐Syn in the CNS are more vulnerable to degeneration caused by deposits of α‐Syn (Masliah et al., 2000). Our results that GABAergic and DA somas were α‐Syn IR indicate that they might be affected in very early stage of PD, perhaps resulting in the abnormality of the OPs and partially b waves reported previously (Veys et al., 2021, Langheinrich et al., 2000). Second, ipRGC cell bodies expressing α‐Syn point out a pathological clue for sleep disorder occurred in PD patients (Do, 2019).…”

“…PD is characterized by the aggregation of misfolded α‐Syn and the loss of dopaminergic (DA) neurons mainly in the substantia nigra and the striatum (Forno, 1996, Kalia & Lang, 2015). Emerging evidence indicates that the retinas of postmortem PD patients and PD mouse models have elevated levels of misfolded α‐Syn (Veys et al., 2021, Ortuño‐Lizarán et al., 2018, Mammadova et al., 2019, Mammadova et al., 2021, Bodis‐Wollner et al., 2014). Therefore, it is important to characterize α‐Syn in the retina to determine its roles in healthy and diseased states.…”

“…On the other hand, pathological results have widely reported visual deficits in PD patients, PD mouse models, and MSA patients (Zhang et al., 2021, Armstrong, 2015). In the case of PD patients, pathological changes including retinal layer thinning and Lewy bodies have been observed in the inner retina, whereas the impairment of retinal neurons (ganglion cells, rod bipolar cells) have been found in the PD mouse model (Veys et al., 2019, Veys et al., 2021, Chorostecki et al., 2015, Ortuño‐Lizarán et al., 2020). Functionally, visual dysfunctions such as loss of contrast sensitivity, impaired visual acuity, complex visual hallucinations, altered electroretinogram (ERG), and disturbed color vision have been reported in patients (Weil et al., 2016, Lee et al., 2014, Price et al., 1992, Archibald et al., 2011, Langheinrich et al., 2000).…”

Age-related dysregulation of the retinal transcriptome in African turquoise killifish

“…Small animals such as mice, rats, and zebrafish have been extensively utilised to study fundamental mechanisms underlying different retinal neurodegenerative diseases (Collin et al, 2020; Koh et al, 2019; Niwa et al, 2016; Noel et al, 2022; Veys et al, 2021). Unfortunately, ageing studies are challenging in mammalian model organisms due to their relatively long lifespan (Kim et al, 2016).…”

Differential reductions in the capillary red-blood-cell flux between retina and brain under chronic global hypoperfusion

“…These neurological disorders are also associated with ocular symptoms that are detectable through ophthalmological examinations; 2 – 7 and the ocular changes often precede the conventional diagnosis of the symptoms in the brain 6 , 8 – 17 The diagnosis of these neurological disorders often involves expensive or invasive methods, such as MRI, PET, and cerebrospinal fluid assessment via spinal tap. Hence, retinal imaging may provide a low-cost and noninvasive alternative for the early diagnosis of neurological disorders 1 …”