Single-Nucleotide Polymorphisms Associated with the Senescence-Accelerated Phenotype of OXYS Rats: A Focus on Alzheimer’s Disease-Like and Age-Related-Macular-Degeneration-Like Pathologies

Abstract

Alzheimer's disease (AD) and age-related macular degeneration (AMD) are two complex incurable neurodegenerative disorders the common pathogenesis of which is actively discussed. There are overlapping risk factors and molecular mechanisms of the two diseases; at the same time, there are arguments in favor of the notion that susceptibility to each of these diseases is associated with a distinct genetic background. Here we identified single-nucleotide polymorphisms (SNPs) that are specific for senescence-accelerated OXYS rats, which simulate key characteristics of both sporadic AD and AMD. Transcriptomes of the hippocampus, prefrontal cortex, and retina (data of RNA-Seq) were analyzed. We detected SNPs in genes Rims2, AABR07072639.2, Lemd2, and AABR07045405.1, which thus can express significantly truncated proteins lacking functionally important domains. Additionally, 33 mutations in genes-which are related to various metabolic and signaling pathways-cause nonsynonymous amino acid substitutions presumably leading to disturbances in protein structure or functions. Some of the genes carrying these SNPs are associated with aging, neurodegenerative, and mental diseases. Thus, we revealed the SNPs can lead to abnormalities in protein structure or functions and affect the development of the senescence-accelerated phenotype of OXYS rats. Our data are consistent with the latest results of genome-wide association studies that highlight the importance of multiple pathways for the pathogenesis of AD and AMD. Identified SNPs can serve as promising research objects for further studies on the molecular mechanisms underlying this particular rat model as well as for the prediction of potential biomarkers of AD and AMD.

Epithelial-Mesenchymal Transition and Senescence in the Retinal Pigment Epithelium of NFE2L2/PGC-1α Double Knock-Out Mice

“…Senescent cells, which are characterized by senescence-associated secretory phenotype (SASP), release factors that can initiate or increase existing low-grade inflammatory processes, which are of special relevance to aging and age-associated diseases both in general and in AMD in particular [35,36]. Senescence-accelerated OXYS rats are an established model of premature aging and of some neurodegenerative diseases, including AMD [37,38].…”

To the question of the digital platform “bioinformatics” creating and its system-forming solutions

“…[34]); animal collections: wild and laboratory animals, live breeding (e.g. [35][36][37][38]); animal collections: museum zoological animal collections; animal collections: farm animals; cell culture collections; microorganism collections (e.g. [39,40]); plant collections: herbarium funds of plants biological diversity; plant collections: living collections of natural flora; plant collections: agricultural plants (e.g.…”

Genetic Determinants Highlight the Existence of Shared Etiopathogenetic Mechanisms Characterizing Age-Related Macular Degeneration and Neurodegenerative Disorders

“…One of the major consequences of the increasing life expectancy worldwide is the higher burden of age-related multifactorial diseases, including neurodegenerative disorders (NDDs) and cardiovascular, metabolic, and retinal disorders (1). In particular, NDDs and retinal disorders include a large spectrum of agerelated conditions characterized by the progressive loss or dysfunction of neurons in specific areas of the central nervous system (CNS) and retina (2,3). As a natural extension of the CNS, the retina shares several similarities with the brain and spinal cord concerning its anatomy, functionality, response to insult, and immunological features (2,4).…”

“…These peculiarities led to refer to the eye as "a window to the brain, " since it can provide substantial information on brain health and disease and can enhance the research of new therapeutic avenues for the treatment of NDDs (2,4). Indeed, both NDDs and age-related retinal disorders are characterized by a similar neurotoxic environment leading to oxidative and metabolic stress, excessive neuro-inflammatory response, mitochondrial dysfunction, and abnormal aggregation of proteins and debris, which, ultimately, cause the degeneration of neurons, photoreceptor cells, retinal ganglion cells, and their related axons (3,4). Among the most investigated retinal disorders, age-related macular degeneration (AMD) showed several aging processes and risk factors in common with NDDs, including cognitive impairment, Alzheimer disease (AD), and Parkinson disease (PD) (2,6).…”