TY - JOUR

T1 - 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

AU - Devyatkin, Vasiliy A.

AU - Redina, Olga E.

AU - Kolosova, Nataliya G.

AU - Muraleva, Natalia A.

N1 - The analysis of transcriptome data from OXYS rats was supported by the Russian Science Foundation [grant #19-15-00044]. The sponsor had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

PY - 2020/1/1

Y1 - 2020/1/1

N2 - 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.

AB - 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.

KW - Age-related macular degeneration

KW - aging

KW - Alzheimer’s disease

KW - senescence-accelerated OXYS rats

KW - SNP

UR - http://www.scopus.com/inward/record.url?scp=85079203929&partnerID=8YFLogxK

U2 - 10.3233/JAD-190956

DO - 10.3233/JAD-190956

M3 - Article

C2 - 31929160

AN - SCOPUS:85079203929

VL - 73

SP - 1167

EP - 1183

JO - Journal of Alzheimer's Disease

JF - Journal of Alzheimer's Disease

SN - 1387-2877

IS - 3

ER -