GSE157713
Dysfunctions in nonsense-mediated decay, protein homeostasis, OXPHOS function, and brain connectivity in ALS-FUS mice with cognitive deficits
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. Overall design: Bulk RNA-Seq of hippocampi of 12-month-old non-transgenic and hFUS-R514G mice