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Dysfunctions in nonsense-mediated decay, protein homeostasis, OXPHOS function, and brain connectivity in ALS-FUS mice with cognitive deficits

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE157713 | GEO | 2021/01/11

REPOSITORIES: GEO

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Project description:Through the generation of humanized FUS mice expressing full length human FUS, we identify that when expressed at near endogenous murine FUS levels both wild-type or ALS- and frontotemporal dementia (FTD)-causing mutations complement the essential function(s) of murine FUS. Replacement of murine FUS with mutant, but not wild-type, human FUS causes stress-mediated induction of chaperones, decreased expression of ion channels/transporters essential for synaptic function, and reduced synaptic activity, without loss of nuclear FUS or its cytoplasmic aggregation. Most strikingly, accumulation of mutant human FUS is shown to activate an integrated stress response and inhibit local, intra-axonal protein synthesis in hippocampal neurons and sciatic nerves. Collectively, our evidence demonstrates that human ALS/FTD-linked mutations in FUS induce a gain-of-toxicity that includes stress-mediated suppression in intra-axonal translation, synaptic dysfunction, and progressive, age-dependent motor and cognitive disease without cytoplasmic aggregation, altered nuclear localization, or aberrant splicing of FUS-bound pre-mRNAs. Methods: RNA from mouse spinal cords of 18-month-old mFUS-/-/hgFUS (WT, R521C or R521H) and their Non-Tg control littermates was extracted with TRIzol. RNA quality was measured using the Agilent Bioanalyzer system and processed using the Illumina TruSeq Stranded mRNA Sample Preparation Kit according to manufacturer’s protocols. mRNA profiles were generated by deep sequencing, with n≥3 biological replicates per group. Results: We mapped on average 15 million non-redundant reads per sample. Fastq files were aligned to mouse reference genome (mm9 UCSC Genome Browser) using TopHat workfow and the transcript abundance for each annotated protein-coding gene [as fragments per kilobase of transcript per million mapped reads (FPKM)] was estimated by Cufflinks. 13,468 genes which expressed FPKM>=1 were kept for downstream analyses. RNA profiles from normal (Non-Tg) and humanized hgFUSWT mice were almost undistinguishable. Both humanized mutant FUS lines had highly distinct RNA profiles [determined with unsupervised hierarchical clustering and principal component analysis (PCA)], with 709 down and 348 up-regulated genes relative to age-matched Non-Tg or humanized hgFUSWT littermates (P<0.05). These changes uncovered FUS mutant dependent altered pathways that may contribute to ALS/FTD-linked mutant FUS-mediated toxicity. The validation by RT-QPCR of altered expression of 20 genes is shown in Figure 5.

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Dysfunctions in nonsense-mediated decay, protein homeostasis, OXPHOS function, and brain connectivity in ALS-FUS mice with cognitive deficits

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