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

Acta Neuropathologica Communications - Tập 9 - Trang 1-24 - 2021
Wan Yun Ho1, Ira Agrawal1, Sheue-Houy Tyan2, Emma Sanford1, Wei-Tang Chang3,4, Kenneth Lim1,5, Jolynn Ong1, Bernice Siu Yan Tan, Aung Aung Kywe Moe6,7, Regina Yu6,7, Peiyan Wong8,9, Greg Tucker-Kellogg5,10, Edward Koo3,11, Kai-Hsiang Chuang3,6,7, Shuo-Chien Ling1,9,12
1Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
2Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
3Agency for Science, Technology and Research, Singapore Bioimaging Consortium, Singapore, Singapore
4University of North Carolina, Chapel Hill, USA
5Computational Biology Programme, Faculty of Science, National University of Singapore, Singapore, Singapore
6Queensland Brain Institute, The University of Queensland, Brisbane, Australia
7Centre for Advanced Imaging, The University of Queensland, Brisbane, Australia
8Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
9Program in Neuroscience and Behavior Disorders, Duke-NUS Medical School, Singapore, Singapore
10Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore, Singapore
11Department of Neurosciences, University of California at San Diego, La Jolla, USA
12Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

Tóm tắt

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.

Tài liệu tham khảo

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