Dysfunction in nonsense-mediated decay, protein homeostasis, mitochondrial function, and brain connectivity in ALS-FUS mice with cognitive deficits.
Wan Yun HoIra AgrawalSheue-Houy TyanEmma SanfordWei-Tang ChangKenneth LimJolynn OngBernice Siu Yan TanAung Aung Kywe MoeRegina YuPeiyan WongGreg Tucker-KelloggEdward KooKai-Hsiang ChuangShuo-Chien LingPublished in: Acta neuropathologica communications (2021)
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent two ends of the same disease spectrum of adult-onset neurodegenerative diseases that affect the motor and cognitive functions, respectively. Multiple common genetic loci such as fused in sarcoma (FUS) have been identified to play a role in ALS and FTD etiology. Current studies indicate that FUS mutations incur gain-of-toxic functions to drive ALS pathogenesis. However, how the disease-linked mutations of FUS affect cognition remains elusive. Using a mouse model expressing an ALS-linked human FUS mutation (R514G-FUS) that mimics endogenous expression patterns, we found that FUS proteins showed an age-dependent accumulation of FUS proteins despite the downregulation of mouse FUS mRNA by the R514G-FUS protein 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 revealed a deregulation of genes that cluster in pathways involved in nonsense-mediated decay, protein homeostasis, and mitochondrial functions. Furthermore, the use of in vivo functional imaging demonstrated widespread reduction in cortical volumes but enhanced functional connectivity between hippocampus, basal ganglia and neocortex in R514G-FUS mice. Hence, our findings suggest that disease-linked mutation in FUS may lead to changes in proteostasis and mitochondrial dysfunction that in turn affect brain structure and connectivity resulting in cognitive deficits.
Keyphrases
- functional connectivity
- amyotrophic lateral sclerosis
- resting state
- white matter
- mouse model
- poor prognosis
- endothelial cells
- binding protein
- high resolution
- oxidative stress
- long non coding rna
- dna methylation
- skeletal muscle
- gene expression
- magnetic resonance
- mild cognitive impairment
- single cell
- cognitive impairment
- metabolic syndrome
- insulin resistance
- wild type
- fluorescent probe