Understanding the dynamics of biological colloids to elucidate cataract formation towards the development of methodology for its early diagnosis
📝 Abstract
The eye lens is the most characteristic example of mammalian tissues exhibiting complex colloidal behaviour. In this paper we briefly describe how dynamics in colloidal suspensions can help addressing selected aspects of lens cataract which is ultimately related to the protein self-assembly under pathological conditions. Results from dynamic light scattering of eye lens homogenates over a wide protein concentration were analyzed and the various relaxation modes were identified in terms of collective and self-diffusion processes. Using this information as an input, the complex relaxation pattern of the intact lens nucleus was rationalized. The model of cold cataract - a phase separation effect of the lens cytoplasm with cooling - was used to simulate lens cataract at in vitro conditions in an effort to determine the parameters of the correlation functions that can be used as reliable indicators of the cataract onset. The applicability of dynamic light scattering as a non-invasive, early-diagnostic tool for ocular diseases is also demonstrated in the light of the findings of the present paper.
💡 Analysis
The eye lens is the most characteristic example of mammalian tissues exhibiting complex colloidal behaviour. In this paper we briefly describe how dynamics in colloidal suspensions can help addressing selected aspects of lens cataract which is ultimately related to the protein self-assembly under pathological conditions. Results from dynamic light scattering of eye lens homogenates over a wide protein concentration were analyzed and the various relaxation modes were identified in terms of collective and self-diffusion processes. Using this information as an input, the complex relaxation pattern of the intact lens nucleus was rationalized. The model of cold cataract - a phase separation effect of the lens cytoplasm with cooling - was used to simulate lens cataract at in vitro conditions in an effort to determine the parameters of the correlation functions that can be used as reliable indicators of the cataract onset. The applicability of dynamic light scattering as a non-invasive, early-diagnostic tool for ocular diseases is also demonstrated in the light of the findings of the present paper.
📄 Content
The physics of colloidal suspensions has seen a great upsurge over the last two decades owing to the numerous theoretical and experimental investigations undertaken [1,2]. The interest has arisen in view of the fact that colloidal suspensions serve as model systems in studies of changes in particles’ interactions in dilute/dense systems, for example the sol-gel transition, as well as in studies of dynamically arrested matter, such as the liquid-glass-transition [3,4]. Implicit in the vast majority of the studies of colloidal suspensions is the investigation of the effect of tuning interparticle interactions either by changing the colloidal particles concentration or by controlling certain properties of the solvent. The rich physical picture that has been gained by such studies has proved useful for understanding the behaviour of more complex systems, i.e. biological colloids. In the latter, and in particular in protein suspensions, one is frequently encountered with certain difficulties, i.e. departure from hard sphere behaviour, polydispersity, and multi-component mixture with highly asymmetric particle sizes, which are factors that complicate their study. This stands as an impediment in comprehending basic mechanisms of tissue functions and the routes to their degradation under pathological conditions. Such pathological conditions emerge frequently in cases where proteins aggregate or condense to form insoluble supra-molecular assemblies [5]. Even small amounts of aggregates can significantly alter the molecular structure which will modify protein function.
Monitoring and understanding these effects are fundamental for resolving the relation of the molecular mechanisms that lead to proteins self-assembly and the effect that this could have to cellular function for the onset or the progress of a related disease. The ocular lens is presumably the most characteristic example of a mammalian tissue that exhibits complex colloidal behaviour. The lens can be considered as a dense aqueous suspension of globular proteins called crystallins (α-, β-, and γ-crystallins) whose total concentration ranges from ~200 mg ml -1 in the lens periphery (cortex) up to ~500 mg ml -1 in the lens nucleus. It is therefore quite surprising that such a concentrated suspension with a dense macromolecular content is highly transparent. Apparently, short-range interactions among crystallins play a decisive role in the underlying lens transparency [6,7]. Lens opacification, usually referred to as cataract, reflects changes in interactions between crystallins and in particular is associated with changes in the shortrange structural order. On general grounds, cataract is any opacification of the lens, which interferes with visual function by producing increased light scattering. Cataract is emerging as one of the most frequent diseases in humankind, being considered today as the most important cause of preventable blindness worldwide. Currently, cataract diagnosis is made clinically at the mature level of the disease. As the life expectancy is gradually increasing, age-related diseases like cataract will become more prominent among the population with high societal impact. It is therefore obvious the need for the development of a tool for early, non-invasive diagnosis of cataract onset.
A thorough understanding of the molecular mechanisms of lens opacification, signifying the onset of cataract, inevitably calls for an appreciation of the interactions between protein “particles” and the aggregation processes that take place upon aging and/or in the presence of other pathogenic factors.
The key point to study interparticle interactions and aggregation is to investigate the diffusion processes of the colloidal particles at various time scales. Knowing that changes of density and/or concentration fluctuations underlie cataract formation and that the spatial dimensions of these fluctuations match to the visible light wavelength, it is rather apparent that dynamic light scattering (DLS) is an ideal tool for studying their dynamics. The added value of DLS studies of diffusion dynamics is that such studies can provide a simple, sensitive, and reliable methodology for noninvasive, early diagnosis of ocular diseases. The transparency of the lens and the other ocular tissues, situated externally to it, e.g. cornea, aqueous humour, as well as the dependence of the scattered intensity on the sixth power of the particle radius add to the advantages of using DLS as an in vivo diagnostic tool for cataract detection. Research efforts in line with the aforementioned ideas were undertaken in the past mainly by Benedek and co-workers; see [7] for a review. However, several other authors have conducted similar light scattering and related spectroscopic studies as has been recently reviewed in [8] and [9]. In particular, DLS has been utilized for in vivo and in vitro studies of intact mammalian lenses. Despite the large body of experimental data the identifi
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