Effects of the NRXN1 haploinsufficiency and the treatment with risperidone in neuronal cells

• Grant number: 15/10636-5
• Support type: Regular Research Grants
• Duration: February 01, 2016 - July 31, 2018
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Elizabeth Suchi Chen
• Grantee: Elizabeth Suchi Chen
• Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Assoc. researchers: Carolina de Oliveira Gigek ; Marilia de Arruda Cardoso Smith

Abstract

Autism spectrum disorders (ASD) refer to the range of developmental disorders that include such behaviors as abnormal social interactions, repetitive behaviors, and impaired communication. It is estimated that the heritability of the disease is 70-90%, and a number of genetic loci have been convincingly linked in independent studies to the disorder such as NRXN1. Notably, no genetic variant has yet been found in any study that can explain more that 1% of cases of ASD, suggesting that ASDs are heterogeneous and complex. Pertinent to the current application, no findings have explained a greater portion of the genetic contribution to ASD than large copy number changes in microdeletion syndrome regions. By studying microdeletion syndrome regions, a link might begin to be made between genotype and phenotype - i.e., what does a particular gene do? How does lack of one copy of the gene impact phenotype? Hence, the evaluation of the haploinsuffiency of these regions is crucial for a better understanding of the molecular mechanisms involved in ASD. Neurexin 1 (NRXN1) is a pre-synaptic protein and has been associated with neurodevelopmental and behavioral traits; however, the genes downstream involved in this pathway are still being discovered. Thus, we aimed to understand how dosage alterations in NRNX1 affect downstream targeting of each using stem cell-derived human neurons. We hypothesize that reduced expression of NRNX1 leads to significant, widespread disruption of the epigenome (miRNA-seq) and transcriptome (RNA-seq) in human neurons. Furthermore, we also aim to identify genomic targets affected by the treatment with risperidone in neurons. We believe that the identification of the targets of each gene in wild-type and dosage-reduced states will reveal a network of genes important in brain development and ASD, as well as to elucidate the molecular pathway of the treatment with risperidone. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

FARIA, TATHYANE C.; MALDONADO, HECTOR L.; SANTOS, LEONARDO C.; DELABIO, ROGER; PAYAO, SPENCER L. M.; TURECKI, GUSTAVO; MECHAWAR, NAGUIB; SANTANA, DALILEIA A.; GIGEK, CAROLINA O.; LEMOS, BERNARDO; SMITH, MARILIA A. C.; CHEN, ELIZABETH S. Characterization of Cerebellum-Specific Ribosomal DNA Epigenetic Modifications in Alzheimer's Disease: Should the Cerebellum Serve as a Control Tissue After All?. Molecular Neurobiology, MAR 2020. Web of Science Citations: 0.