The objective of the proposed research is to translate genetic findings to potential treatment options for the psychiatric disorders autism spectrum disorder (ASD) and schizophrenia (SCZ). Genome-wide association studies (GWASs) are designed to identify novel genes and pathways that contribute to complex disorder risk. Application of GWAS to ASD and SCZ identified highly significant genetic association of the non-coding RNAs (ncRNAs) MSNP1AS (moesin pseudogene 1, antisense;P=10-10 with ASD) and MIR137 (microRNA 137;P=10-11 with SCZ). We discovered MSNP1AS and reported that its expression in human cerebral cortex is increased 12.7-fold in individuals with ASD and increased 22-fold in individuals with the ASD-associated genetic marker. Over-expression of the MSNP1AS ncRNA in human neuronal cell lines caused significant decreases in the X chromosome gene moesin (MSN) mRNA, moesin protein, neurite number and neurite length. Moesin influences stability of neuronal processes and immune response, and is thus an excellent biological candidate to explain the decreased long-distance connectivity observed in the brains of individuals with ASD. For SCZ, MIR137 is one of seven loci with genome-wide significant association. Four of the other six SCZ genes with genome-wide significant association (P<5 x 10-8) are targets of MIR137, and over-expression of MIR137 resulted in decreased transcription from these target gene sequences. Experiments in rat hippocampal neurons indicated that over-expression of MIR137 causes a decrease in neurite length. Therefore, both MSNP1AS and MIR137 have similar impacts on neuronal morphology. We hypothesize that over-expression of the MSNP1AS and MIR137 ncRNAs causes an overlapping change in gene expression that contributes to the common altered neuronal function. This proposal brings together experts in ncRNA from three distinct fields (psychiatry, HIV research, and prostate cancer research) to determine the biological impact of the ASD- and SCZ-associated ncRNAs on human neuronal cells.
Aim 1 will use an innovative RNA-Seq approach to determine the protein-coding and ncRNA transcripts with altered expression in human neuronal cell lines caused by over-expression of MSNP1AS or MIR137.
Aim 2 will determine the most effective antisense-to-the-antisense approaches for decreasing expression of MSNP1AS and MIR137 in human neuronal cell lines.
Aim 3 will determine the impact of altered expression of MSNP1AS and MIR137 on neuronal morphology in human neuronal cell lines. This work represents the critical 'post-GWAS'translation of genetic findings to an understanding of their biological consequences and establishes a platform for analysis of ncRNAs in neurodevelopmental disorders. Antisense approaches have proven effective in the treatment of cancer and HIV. Although developmental brain disorders introduce unique challenges, the antisense-to-the- antisense approach may also prove effective for some patients with ASD and SCZ.
Public Health Relevance Statement Autism spectrum disorder and schizophrenia are neurodevelopmental disorders that affect ~1% of the population. Recent genome-wide association studies provided strong genetic evidence that the non-coding RNAs MSNP1AS and MIR137 contribute to risk for these disorders. This research proposal will investigate the biological impact of these non-coding RNAs on gene expression and neuronal architecture in human neuronal cells.