ArticleActa neuropathologica communications2021
Dysfunction in nonsense-mediated decay, protein homeostasis, mitochondrial function, and brain connectivity in ALS-FUS mice with cognitive deficits.
Article in Acta neuropathologica communications, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 28 citations in OpenAlex.
- Misfolded Proteins and Cognitive Decline: Mechanistic Insights into Neurodegenerative Disorders.Neurology international · 2026Review
- Nonsense-Mediated mRNA Decay: Mechanisms and Recent Implications in Cardiovascular Diseases.Cells · 2025Review
- DNA methylation signature of a lifestyle-based resilience index for cognitive health.Alzheimer's research & therapy · 2025Article
- Longitudinal multi-omics in alpha-synuclein Drosophila model discriminates disease- from age-associated pathologies in Parkinson's disease.NPJ Parkinson's disease · 2025Article
- Mild cognitive impairment in amyotrophic lateral sclerosis: current view.Journal of neural transmission (Vienna, Austria : 1996) · 2025Review
- Reversal of cognitive deficits in FUSNeurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2024Article
- Molecular hallmarks of ageing in amyotrophic lateral sclerosis.Cellular and molecular life sciences : CMLS · 2024Review
- FUS-dependent microRNA deregulations identify TRIB2 as a druggable target for ALS motor neurons.iScience · 2023Article
- Neuronal dysfunction caused by FUSR521G promotes ALS-associated phenotypes that are attenuated by NF-κB inhibition.Acta neuropathologica communications · 2023Article
- The Spectrum of Cognitive Dysfunction in Amyotrophic Lateral Sclerosis: An Update.International journal of molecular sciences · 2023Review
- Review
- Article
- Synaptic Dysfunction and Plasticity in Amyotrophic Lateral Sclerosis.International journal of molecular sciences · 2023Review
- A postzygotic de novo NCDN mutation identified in a sporadic FTLD patient results in neurochondrin haploinsufficiency and altered FUS granule dynamics.Acta neuropathologica communications · 2022Article
- Synaptic dysfunction in ALS and FTD: anatomical and molecular changes provide insights into mechanisms of disease.Frontiers in molecular neuroscience · 2022Review
- Current Concepts on Genetic Aspects of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis.International journal of molecular sciences · 2021Review
- Disruption of orbitofrontal-hypothalamic projections in a murine ALS model and in human patients.Translational neurodegeneration · 2021Article
- Reactive astrocytes in ALS display diminished intron retention.Nucleic acids research · 2021Article
- The Interplay of RNA Binding Proteins, Oxidative Stress and Mitochondrial Dysfunction in ALS.Antioxidants (Basel, Switzerland) · 2021Review
Corrections and comments
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Authors and funding
15 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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