Person:

Wertz, Mary H

Background: Fragile X syndrome and tuberous sclerosis are genetic syndromes that both have a high rate of comorbidity with autism spectrum disorder (ASD). Several lines of evidence suggest that these two monogenic disorders may converge at a molecular level through the dysfunction of activity-dependent synaptic plasticity. Methods: To explore the characteristics of transcriptomic changes in these monogenic disorders, we profiled genome-wide gene expression levels in cerebellum and blood from murine models of fragile X syndrome and tuberous sclerosis. Results: Differentially expressed genes and enriched pathways were distinct for the two murine models examined, with the exception of immune response-related pathways. In the cerebellum of the Fmr1 knockout (Fmr1-KO) model, the neuroactive ligand receptor interaction pathway and gene sets associated with synaptic plasticity such as long-term potentiation, gap junction, and axon guidance were the most significantly perturbed pathways. The phosphatidylinositol signaling pathway was significantly dysregulated in both cerebellum and blood of Fmr1-KO mice. In Tsc2 heterozygous (+/−) mice, immune system-related pathways, genes encoding ribosomal proteins, and glycolipid metabolism pathways were significantly changed in both tissues. Conclusions: Our data suggest that distinct molecular pathways may be involved in ASD with known but different genetic causes and that blood gene expression profiles of Fmr1-KO and Tsc2+/− mice mirror some, but not all, of the perturbed molecular pathways in the brain.

Spinal Muscular Atrophy (SMA) is a devastating autosomal-recessive pediatric neurodegenerative disease characterized by loss of spinal motor neurons. It is caused by mutation in the survival of motor neuron 1, SMN1, gene and leads to loss of function of the full-length SMN protein. SMN has a number of functions related to RNA processing in neurons, including RNA trafficking in neurites, and RNA splicing and snRNP biogenesis in the nucleus. While previous work has focused on the alternative splicing and expression of traditional mRNAs, our lab has focused on the contribution of another RNA species, microRNAs (miRNAs), to the SMA phenotype. miRNAs are ~22 nucleotide small RNAs that are involved in post-transcriptional regulation of gene expression. They function by translational repression or mRNA decay of target RNAs. Interestingly, dysregulation of RNA processing and miRNA expression has been identified in motor neuron diseases including SMA and Amyotrophic Lateral Sclerosis. Our lab previously discovered a miRNA, miR-183, that is dysregulated in SMA and impacts its targets in cortical neurons and SMA mouse spinal cords. However, spinal motor neurons are the cell type most affected by SMN loss. We hypothesized that motor neuron specific miRNA changes are involved selective vulnerability in SMA. Therefore, we sought to determine the effect of loss of SMN on spinal motor neurons. To accomplish this, I used microarray and RNAseq to profile both miRNA and mRNA expression in primary spinal motor neurons after acute SMN knockdown. By integrating the miRNA:mRNA profiles we identified dysregulated miRNAs with enrichment in differentially expressed putative targets. miR-431 was the most substantially increased miRNA and a number of its putative targets were downregulated after SMN loss. Further, I confirm that miR-431 directly regulates its target chondrolectin and impacts neurite length. This work is critical to understanding the cell-type specific effect of aberrant miRNA expression in SMN knockdown motor neurons. It demonstrates the contribution of dysregulated RNA processing in motor neurons to neurodegeneration. Furthermore, this work highlights the impact of non-coding RNAs in human disease and points to specific miRNA whose dysregulation potentially impacts motor neuron health.