Investigating G-quadruplex structures in RPGR gene: Implications for understanding X-linked retinal degeneration.

Aims: This pilot study investigates the potential pathogenic role of G-quadruplex (G4) structures in RPGR-associated retinal degeneration, starting from a case of suspected X-linked form affected family. We hypothesize that the stabilization of these structures might alter DNA replication and transcription, inducing genetic instability and influencing gene expression. Main methods: We conducted whole genome amplification experiments and next-generation sequencing to detect the blockade of polymerase activity by G4 structures. Our specific focus was the RPGR gene, which hosts a high concentration of predicted G4-forming motifs and is implicated in most X-linked retinal degeneration cases. To understand the potential interference of G4 structures, we applied computational and 3D molecular modeling to visualize interferences in DNA replication and transcription regulation. Key findings: Our data confirmed the obstruction of DNA polymerase enzymes by G4 structures, particularly when stabilized by the compound pyridostatin. This obstruction was evident in the reduced amplification of RPGR gene regions and a shift in the start/end sites of putative G4 motifs. Moreover, the modeling indicated a potential disruption of critical promoter elements and RNA polymerase binding, which could drastically alter gene expression. Significance: Our findings suggest that G4 formation in the RPGR gene could lead to genetic instability and affect the expression of RPGR, contributing to retinal dystrophy. Moreover, this study underscores the broader implications of G4 structures in other genetic disorders. Improved understanding of G4 structures could reveal novel therapeutic targets to combat genetic disorders, promoting the advancement of personalized medicine and precision health.

From powerhouse to regulator: The role of mitoepigenetics in mitochondrion-related cellular functions and human diseases.

Beyond their crucial role in energy production, mitochondria harbor a distinct genome subject to epigenetic regulation akin to that of nuclear DNA. This paper delves into the nascent but rapidly evolving fields of mitoepigenetics and mitoepigenomics, exploring the sophisticated regulatory mechanisms governing mitochondrial DNA (mtDNA). These mechanisms encompass mtDNA methylation, the influence of non-coding RNAs (ncRNAs), and post-translational modifications of mitochondrial proteins. Together, these epigenetic modifications meticulously coordinate mitochondrial gene transcription, replication, and metabolism, thereby calibrating mitochondrial function in response to the dynamic interplay of intracellular needs and environmental stimuli. Notably, the dysregulation of mitoepigenetic pathways is increasingly implicated in mitochondrial dysfunction and a spectrum of human pathologies, including neurodegenerative diseases, cancer, metabolic disorders, and cardiovascular conditions. This comprehensive review synthesizes the current state of knowledge, emphasizing recent breakthroughs and innovations in the field. It discusses the potential of high-resolution mitochondrial epigenome mapping, the diagnostic and prognostic utility of blood or tissue mtDNA epigenetic markers, and the promising horizon of mitochondrial epigenetic drugs. Furthermore, it explores the transformative potential of mitoepigenetics and mitoepigenomics in precision medicine. Exploiting a theragnostic approach to maintaining mitochondrial allostasis, this paper underscores the pivotal role of mitochondrial epigenetics in charting new frontiers in medical science.

Bridging Retinal and Cerebral Neurodegeneration: A Focus on Crosslinks between Alzheimer-Perusini's Disease and Retinal Dystrophies.

In the early stages of Alzheimer-Perusini's disease (AD), individuals often experience vision-related issues such as color vision impairment, reduced contrast sensitivity, and visual acuity problems. As the disease progresses, there is a connection with glaucoma and age-related macular degeneration (AMD) leading to retinal cell death. The retina's involvement suggests a link with the hippocampus, where most AD forms start. A thinning of the retinal nerve fiber layer (RNFL) due to the loss of retinal ganglion cells (RGCs) is seen as a potential AD diagnostic marker using electroretinography (ERG) and optical coherence tomography (OCT). Amyloid beta fragments (Aß), found in the eye's vitreous and aqueous humor, are also present in the cerebrospinal fluid (CSF) and accumulate in the retina. Aß is known to cause tau hyperphosphorylation, leading to its buildup in various retinal layers. However, diseases like AD are now seen as mixed proteinopathies, with deposits of the prion protein (PrP) and α-synuclein found in affected brains and retinas. Glial cells, especially microglial cells, play a crucial role in these diseases, maintaining immunoproteostasis. Studies have shown similarities between retinal and brain microglia in terms of transcription factor expression and morphotypes. All these findings constitute a good start to achieving better comprehension of neurodegeneration in both the eye and the brain. New insights will be able to bring the scientific community closer to specific disease-modifying therapies.

Human retinal secretome: A cross-link between mesenchymal and retinal cells.

In recent years, mesenchymal stem cells (MSC) have been considered the most effective source for regenerative medicine, especially due to released soluble paracrine bioactive components and extracellular vesicles. These factors, collectively called the secretome, play crucial roles in immunomodulation and in improving survival and regeneration capabilities of injured tissue. Recently, there has been a growing interest in the secretome released by retinal cytotypes, especially retinal pigment epithelium and Müller glia cells. The latter trophic factors represent the key to preserving morphofunctional integrity of the retina, regulating biological pathways involved in survival, function and responding to injury. Furthermore, these factors can play a pivotal role in onset and progression of retinal diseases after damage of cell secretory function. In this review, we delineated the importance of cross-talk between MSCs and retinal cells, focusing on common/induced secreted factors, during experimental therapy for retinal diseases. The cross-link between the MSC and retinal cell secretomes suggests that the MSC secretome can modulate the retinal cell secretome and vice versa. For example, the MSC secretome can protect retinal cells from degeneration by reducing oxidative stress, autophagy and programmed cell death. Conversely, the retinal cell secretome can influence the MSC secretome by inducing changes in MSC gene expression and phenotype.

How Many Alzheimer-Perusini's Atypical Forms Do We Still Have to Discover?

Alzheimer-Perusini's (AD) disease represents the most spread dementia around the world and constitutes a serious problem for public health. It was first described by the two physicians from whom it took its name. Nowadays, we have extensively expanded our knowledge about this disease. Starting from a merely clinical and histopathologic description, we have now reached better molecular comprehension. For instance, we passed from an old conceptualization of the disease based on plaques and tangles to a more modern vision of mixed proteinopathy in a one-to-one relationship with an alteration of specific glial and neuronal phenotypes. However, no disease-modifying therapies are yet available. It is likely that the only way to find a few "magic bullets" is to deepen this aspect more and more until we are able to draw up specific molecular profiles for single AD cases. This review reports the most recent classifications of AD atypical variants in order to summarize all the clinical evidence using several discrimina (for example, post mortem neurofibrillary tangle density, cerebral atrophy, or FDG-PET studies). The better defined four atypical forms are posterior cortical atrophy (PCA), logopenic variant of primary progressive aphasia (LvPPA), behavioral/dysexecutive variant and AD with corticobasal degeneration (CBS). Moreover, we discuss the usefulness of such classifications before outlining the molecular-genetic aspects focusing on microglial activity or, more generally, immune system control of neuroinflammation and neurodegeneration.