Progressive accumulation of α-Synuclein (αSyn) in Lewy bodies (LBs) and loss of dopaminergic (DA) neurons are the hallmark pathological features of Parkinson’s disease (PD). Although currently available in vitro and in vivo models have provided crucial information about PD pathogenesis, the mechanistic link between the progressive accumulation of αSyn into LBs and the loss of DA neurons is still unclear. To address this, it is critical to model LB formation and DA neuron loss, the two key neuropathological aspects of PD, in a relevant in vitro system. In this study, we developed a human midbrain-like organoid (hMBO) model of PD. We demonstrated that hMBOs generated from induced pluripotent stem cells (hiPSCs), derived from a familial PD (fPD) patient carrying αSyn gene (SNCA) triplication accumulate pathological αSyn over time. These cytoplasmic inclusions spatially and morphologically resembled diverse stages of LB formation and were composed of key markers of LBs. Importantly, the progressive accumulation of pathological αSyn was paralleled by the loss of DA neurons and elevated apoptosis. The model developed in this study will complement the existing in vitro models of PD and will provide a unique platform to study the spatiotemporal events governing LB formation and their relation with neurodegeneration. Furthermore, this model will also be beneficial for in vitro screening and the development of therapeutic compounds.

The neural retina and retinal pigment epithelium (RPE) maintain a symbiotic metabolic relationship, disruption of which leads to debilitating vision loss. The current study was undertaken to identify the differences in the steady-state metabolite levels and the pathways functioning between bona fide neural retina and RPE. Global metabolomics and cluster analyses identified 650 metabolites differentially modulated between the murine neural retina and RPE. Of these, 387 and 163 were higher in the RPE and the neural retina, respectively. Further analysis coupled with transcript and protein level investigations revealed that under normal physiological conditions, the RPE utilizes the pentose phosphate (>3-fold in RPE), serine (>10-fold in RPE), and sphingomyelin biosynthesis (>5-fold in RPE) pathways. Conversely, the neural retina relied mostly on glycolysis. These results show how the RPE and the neural retina have acquired an efficient, complementary and metabolically diverse symbiotic niche to support each other's distinct functions.

In the past, the importance of serine to pathologic or physiologic anomalies was inadequately addressed. Omics research has significantly advanced in the last two decades, and metabolomic data of various tissues has finally brought serine metabolism to the forefront of metabolic research, primarily for its varied role throughout the central nervous system. The retina is one of the most complex neuronal tissues with a multitude of functions. Although recent studies have highlighted the importance of free serine and its derivatives to retinal homeostasis, currently few reviews exist that comprehensively analyze the topic. Here, we address this gap by emphasizing how and why the de novo production and demand for serine is exceptionally elevated in the retina. Many basic physiological functions of the retina require serine. Serine-derived sphingolipids and phosphatidylserine for phagocytosis by the retinal pigment epithelium (RPE) and neuronal crosstalk of the inner retina via D-serine require proper serine metabolism. Moreover, serine is involved in sphingolipid–ceramide balance for both the outer retina and the RPE and the reductive currency generation for the RPE via serine biosynthesis. Finally and perhaps the most vital part of serine metabolism is free radical scavenging in the entire retina via serine-derived scavengers like glycine and GSH. It is hard to imagine that a single tissue could have such a broad and extensive dependency on serine homeostasis. Any dysregulation in serine mechanisms can result in a wide spectrum of retinopathies. Therefore, most critically, this review provides a strong argument for the exploration of serine-based clinical interventions for retinal pathologies.

Derivatives of the vitamin riboflavin, FAD and FMN, are essential cofactors in a multitude of bio-energetic reactions, indispensable for lipid metabolism and also are requisites in mitigating oxidative stress. Given that a balance between all these processes contributes to the maintenance of retinal homeostasis, effective regulation of riboflavin levels in the retina is paramount. However, various genetic and dietary factors have brought to fore pathological conditions that co-occur with a suboptimal level of flavins in the retina. Our focus in this review is to, comprehensively summarize all the possible metabolic and oxidative reactions which have been implicated in various retinal pathologies and to highlight the contribution flavins may have played in these. Recent research has found a sensitive method of measuring flavins in both diseased and healthy retina, presence of a novel flavin binding protein exclusively expressed in the retina, and the presence of flavin specific transporters in both the inner and outer blood-retina barriers. In light of these exciting findings, it is even more imperative to shift our focus on how the retina regulates its flavin homeostasis and what happens when this is disrupted.

The interface between the neural retina and the retinal pigment epithelium (RPE) is critical for several processes, including visual pigment regeneration and retinal attachment to the RPE. One of its most important functions is the exchange of metabolites between the photoreceptors and RPE because photoreceptor cells have very high energy demands, largely satisfied by oxidative metabolism. The riboflavin (RF) cofactors, flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) are two key cofactors involved in oxidative metabolism. We have previously shown that retbindin is a photoreceptor-specific RF-binding protein exclusively expressed in the rods and present in the inter-photoreceptor matrix at the interface between the RPE and photoreceptor outer segments. Here, we show that retbindin ablation in mice causes a retinal phenotype characterized by time- and dose-dependent declines in rod and cone photoreceptor functions as early as 120 days of age. While minor retinal ultrastructural defects were observed at all ages examined, a significant decline occurred in photoreceptor nuclei at 240 days of age (~36.8% rods and ~19.9% cones). Interestingly, significant reductions in FAD and FMN levels were observed before the onset of degeneration (~46.1% FAD and ~45% FMN). These findings suggest that the reduced levels of these flavins result in the disruption of intracellular mechanisms, leading to photoreceptor cell death. Altogether, our results suggest that retbindin is a key player in the acquisition and retention of flavins in the neural retina, warranting future investigation into retbindin s role in photoreceptor cell death in models of retinal degenerative disorders.