FUS-mediated dysregulation of Sema5a, an autism-related gene, in FUS mice with hippocampus-dependent cognitive deficits
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA557350 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9860254.fastq.gz | Fastqsanger.gz | |||
| SRR9860255.fastq.gz | Fastqsanger.gz | |||
| SRR9860256.fastq.gz | Fastqsanger.gz | |||
| SRR9860257.fastq.gz | Fastqsanger.gz | |||
| SRR9860258.fastq.gz | Fastqsanger.gz |
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Project description:Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent two ends of the same disease spectrum of adult-onset neurodegenerative diseases that affect the spinal cord and neocortex, respectively. Multiple common genetic loci such as FUS (fused-in-sarcoma) have been identified to have a role in ALS and FTD aetiology. Current work indicates that FUS mutations incur gain-of-toxic functions to drive ALS pathogenesis. However, how the disease-linked mutations of FUS may affect cognition remains elusive. Using a mouse model expressing an ALS-linked FUS mutation (R514G) that mimics mouse endogenous expression patterns, we found that FUS proteins showed an age-dependent accumulation despite the fact that the R514G protein was able to down-regulate mouse FUS mRNA during aging. Furthermore, these mice developed cognitive deficits accompanied by a reduction in spine density and long-term potentiation (LTP) within the hippocampus. At the physiological expression level, mutant FUS is distributed in the nucleus and cytosol without apparent FUS aggregates or nuclear envelope defects. Unbiased transcriptomic analysis reveals downregulated genes clustered in pathways involved in protein homeostasis, including components of ribosomal proteins and ubiquitin-proteasome pathway, and mitochondrial functions. Furthermore, using in vivo functional imaging, we uncovered that R514G mice exhibited widespread reduction in cortical volumes, yet enhanced functional connectivity between hippocampus, basal ganglia and neocortex. Taken together, our data suggest that disease-linked mutation in FUS may lead to change in proteostasis and dysfunctional mitochondria, which in turns affect brain structure and connectivity resulting in cognitive deficits.
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Project description:Microexons represent the most highly conserved class of alternative splicing, yet their functions are poorly understood. Here, we focus on closely related neuronal microexons overlapping prion-like domains in the translation initiation factors, eIF4G1 and eIF4G3, the splicing of which is activity-dependent and frequently disrupted in autism. CRISPR-Cas9 deletion of these microexons selectively up-regulates synaptic proteins that control neuronal activity and plasticity and further triggers a gene expression program mirroring that of activated neurons. Mice lacking the Eif4g1 microexon display social behavior, learning and memory deficits, as well as alterations in hippocampal synaptic plasticity. The eIF4G microexons appear to reduce synaptic protein synthesis by causing ribosome stalling, through a mechanism whereby they promote the coalescence of cytoplasmic granule components associated with translation repression, including the Fragile X mental retardation protein, FMRP. The results thus reveal an autism-disrupted mechanism by which alternative splicing specializes translation to control higher-order cognitive functioning.
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