NOTCH1 GENE VARIANTS AS BIOMARKERS FOR NEUROCOGNITIVE DISORDER
Name: ALDA DOS SANTOS RODRIGUES
Publication date: 26/03/2025
Examining board:
Name |
Role |
|---|---|
| ELDAMARIA DE VARGAS WOLFGRAMM DOS SANTOS | Examinador Interno |
| ESTEVÃO CARLOS SILVA BARCELOS | Examinador Externo |
| FLAVIA DE PAULA | Coorientador |
| FLAVIA IMBROISI VALLE ERRERA | Presidente |
Summary: Major neurocognitive disorder (MCD), or dementia, has been associated with different risk factors, such as metabolic diseases (diabetes, obesity), stroke, tobacco and alcohol. Genetic factors have been investigated, but are not yet fully understood. The
NOTCH1 gene has 16 transcripts, being expressed in several tissues, mainly cerebral cortex, hippocampus and cerebellum, hematopoietic stem cells, heart and blood vessels, and is associated with 118 phenotypes. NOTCH1 is a protein homologous to
the neurogenic NOTCH locus in humans (Homo sapiens). It is important for glucose homeostasis, growth, lipid and carbohydrate metabolism and cell survival. This signaling pathway has a major impact on the development and maintenance of adequate neuronal function in the human brain. Neurogenesis, being implicated in dementia. Recent evidence points to a shared genetic architecture between metabolic alterations and the theory of Neurocognitive Disorder (NCD). Tau protein and Notch1 are related. NOTCH1 is expressed in the mature human hippocampus, NOTCH1 shows increased immunoreactivity in Alzheimer's disease (AD), and in cases with tau-positive Pick bodies. The absence of NOTCH1 is capable of affecting a cascade of secondary messengers associated with plasticity and spatial learning, also associated with obesity, stroke and, more recently, with reduced volume of brain regions, is associated with the risk of TNC. The hypothesis of this work is that variants in this gene are associated with TNC. The objective is to verify whether variants in NOTCH1 are associated with TNC. Participants in the PAHO study "Health, Well-being and Aging" (SABE) from São Paulo, with complete data (age, sex, T2DM, obesity and stroke) (N=1103), were classified for TNC using the score obtained in the Mini Mental State Examination (MMSE). Participants who scored below the MMSE cutoff line (13 points) were considered to have TNC (N=152). Clinical data were obtained from a standardized questionnaire and genetic data from whole genome sequencing to identify genetic variants. We filtered genotypes, variants and frequency from the Brazilian Online Mutation Archive (ABraOM). The prevalence of TNC was 13.78% (152 patients), the remaining participants (951) were used as controls. Females comprised the majority of the population, corresponding to 64.09% (N=707).
The variants rs10870087, rs2990585, rs7874114 and rs7864342 were identified in DNA regulatory regions, mainly in active enhancers, suggesting their role in the regulation of gene expression, especially in brain tissues. The rs2990585 and rs7874114 variants have epigenetic marks (H3K27ac and H3K4me1), indicating involvement in the activation of genes related to synaptic plasticity and neurodevelopment. rs7864342, associated with microRNA 4674, presents epigenetic marks in blood and cardiac tissues, suggesting tissue-specific regulation. RegulomeDB classified rs2990585 with a high probability of regulatory function (1f), binding to the CEBPA gene, involved in cell differentiation and inflammatory response. Enhancer 2 of this variant is active in several brain regions, such as the midbrain and frontal cortex. In GTEx, rs10870087, rs7864342 and rs7874114 demonstrated eQTL activity for CYSRT1 in breast tissue, while rs2990585 presented eQTLs in genes such as NOTCH1 (blood and tibial artery) and NRARP (lymphocytes). These findings suggest an impact on gene regulation and a possible influence on neurodegenerative
diseases, requiring further studies for confirmation.
