Structural analysis of BACE1-AS in Alzheimer's Disease

• Grant number: 19/12645-2
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): November 01, 2019
• Effective date (End): October 31, 2020
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Silvana Giuliatti
• Grantee: Beatriz Miranda
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Recognition of the functions that long noncoding RNAs (lncRNA) have played in various diseases, including cancer, cardiovascular and neurological disorders, has generated an interest in these structures, since they can provide new diagnoses and opportunities for new therapies, since they present a versatility biochemistry. The functional versatility of lncRNAs range from the ability to perform conformations of different structures to interactions with proteins, DNA and RNA. The constant growth in the number of available RNAs (1,465 in 2019) does not follow the growth in the number of resolved structures (22 in 2019). Approaches other than the experimental ones need to be employed with the great aim of helping to accelerate this learning process. This is also one of the main objectives of the application of Structural Bioinformatics. In neurodegenetative diseases such as Alzheimer's and Parkinson's, there is also evidence of lncRNA assessing brain development, function, maintenance and neuronal differentiation. For these diseases, so far, there is no curative treatment or surgery, but only those that can slow the progress of diseases. Moreover, due to the increasing age of the world population, these neurodegenerative diseases represent an increase in the financial expenses destined for public health. Therefore, there is an urgent need in the development of new methods for prevention or cure of neurodegenerative diseases. Several specific lncRNAS appear to be dysregulated in Alzheimer's Disease (AD), some of which have been implicated in the regulation of AD-related genes, and are involved in A² plaque formation, neuro inflammation, oxidative stress and DNA damage. Studies have reported that beta-secretase 1 (BACE1) is an enzyme that contributes to the formation of A² peptides and deposition of amyloid plaques. BACE1-AS is a transcript by RNA polymerase II of the BACE1 antisense strand. BACE1-AS is highly expressed in patients with AD. It is able to regulate the expressions of BACE1 mRNA and its proteins both in vivo and in vitro. By regulating the expression of BACE1 mRNA, BACE1-AS lncRNA becomes important in the control of AD. In addition, BACE1-AS was found to be increased in human plasma from patients with AD with high specificity. Thus BACE1-AS has been indicated as a possible biomarker and therapeutic target for AD. Therefore, this project aims to analyze the secondary and tertiary structures of BACE1-AS lncRNA, whose performance in Alzheimer's disease is well reported in the literature.