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The eye as a window to the brain: Retinal phenotyping of Parkinson’s disease mouse models

Book - Dissertation

While we live in an ageing society, the prevalence of age-related pathologies is on the rise. Accordingly, the number of patients with neurodegenerative diseases such as Parkinson's disease (PD) is increasing. Despite intensive research efforts into the disease mechanisms underlying PD, no curative therapies are available. The current belief is that, to close this treatment gap, one should aim for prevention of the grave neuronal loss by focussing on early diagnosis, thereby opening a time window for effective neuroprotective treatment. Importantly, biomedical advances go hand in hand with fundamental research of the underlying disease processes, and animal models are essential to complement patient research. An ideal PD model has high face validity, construct validity as well as predictive validity, i.e. it replicates the human PD phenotype as much as possible, is based on a recognised causal factor of the disease, and is responsive to current PD treatment strategies, such as dopamine replacement. Most available animal models mainly focus on brain pathology, since PD is traditionally merely seen as a classical brain disease, yet other parts of the central nervous system remain largely unexplored. In this thesis, we propose that the eye can be seen as a "window to the brain" and we introduce the mouse retina and the visual system as a valuable model to study PD. In contrast to the brain, the retina is directly visible via the pupil and through the transparent optics of the eye, enabling the use of high-resolution in vivo imaging techniques, which can discriminate retinal processes at a micrometre resolution. The retina is not only the most accessible part of the central nervous system, its molecular function and cellular morphology strongly resemble those of the brain and are well-conserved among vertebrates. In addition, the link between the eye and the brain is not only physical, via the optic nerve, but also in terms of similarities in anatomy and pathophysiological processes. Hence, we propose to focus on the retina-brain axis and on the retinal manifestations of PD to (i) unravel the underlying cellular and molecular changes leading to PD pathology, (ii) elucidate the prion-like seeding and spreading capacities of α-synuclein (α-syn), and (iii) shed light on the use of retinal (phospho-)α-syn deposition and hyperspectral imaging as a retinal PD biomarker. First, detailed in vivo functional and morphological analyses combined with post mortem (immuno)histochemical techniques are employed to characterise the retina of the well-established transgenic Thy1-h[A30P]α-syn mouse model. Here, we show that despite the lack of dopaminergic neurodegeneration and neuroinflammation, the retina of the Thy1-h[A30P]α-syn mouse model is characterised by synapse loss and neuronal dysfunction and can provide a platform for research of the early, preclinical/prodromal stages of PD. Subsequently, the use of novel retinal PD models based on the local overexpression of α-syn species in the retina is addressed. Using intravitreal delivery approaches of either viral vectors with an α-syn overexpression construct or α-syn preformed fibrils, we did not succeed in demonstrating a strong, stable and reproducible retinal PD pathology. However, mitigation strategies are formulated to overcome these hurdles, in order to create better models that could serve as (i) a research tool to investigate PD pathogenesis, (ii) a screening tool for new therapeutics and retinal biomarkers and (iii) an anterograde seeding model to study transsynaptic spreading. Further study of the Thy1-h[A30P]α-syn mouse model in this PhD project is part of a research track on PD (and Alzheimer's disease) biomarker discovery, and explored the use of ex vivo hyperspectral imaging of retina of this transgenic mouse to assess retinal α-syn burden. Initial preclinical studies with this high-resolution, non-invasive, label-free imaging technique, uncovered distinct Aβ, ⍺-syn and tau HSI signatures. As such, these first steps of hyperspectral imaging in the PD field suggest that retinal hyperspectral imaging has potential to become a valuable biomarker for abnormal protein accumulation. In summary, this PhD thesis sheds light on the impact of PD on the retina, thereby contributing to the development of novel models to study the cellular and molecular mechanisms underlying PD, and of better methods for diagnosis and follow-up of PD and other neurodegenerative proteinopathies.
Publication year:2021