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

Wan Yun Ho,Wei-Tang Chang,Shuo-Chien Ling,Edward Koo,Kenneth Lim,Bernice Siu Yan Tan,Kai-Hsiang Chuang,Sheue-Houy Tyan,Jolynn Ong,Aung Aung Kywe Moe,Ira Agrawal,Greg Tucker-Kellogg,Regina Yu,Emma Sanford,Peiyan Wong

doi:10.1186/s40478-020-01111-4

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 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.

Highlights

Since 2009, more than 60 mutations in fused in sarcoma (FUS), known as translocated in liposarcoma (TLS), have been identified to be associated with the two overlapping adult-onset neurodegenerative diseases: amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) [1, 2]
Our data suggest that disease-linked mutation in FUS may lead to change in nonsense-mediated decay (NMD), proteostasis and mitochondrial functions, which in turn affect brain structure and connectivity resulting in cognitive deficits
As pathological FUS inclusions are observed in the hippocampus of FTD patients [7, 8], we have previously shown that mice expressing wild-type human FUS at physiological levels developed progressive deficits in hippocampus-mediated cognition tests [49]

Summary

Introduction

Since 2009, more than 60 mutations in fused in sarcoma (FUS), known as translocated in liposarcoma (TLS), have been identified to be associated with the two overlapping adult-onset neurodegenerative diseases: amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) [1, 2]. FUS aggregates were originally found in ALS patients with FUS mutations [3, 4], abnormal FUS inclusions and increased cytosolic FUS have been found in sporadic ALS patients [5, 6] and a subgroup of FTD patients without FUS mutations [7, 8]. This genetic and pathological data indicate that FUS dysfunction may be a common convergent pathway that leads to ALS and FTD. FUS participates in biogenesis and processing of nuclear mRNAs, but it is involved in dendritic and axonal mRNA transport and localized translation, that are important for regulating synaptic plasticity and integrity

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