ArticleHuman molecular genetics2018
Mitochondrial abnormalities and disruption of the neuromuscular junction precede the clinical phenotype and motor neuron loss in hFUSWT transgenic mice.
Article in Human molecular genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 65 papers.
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Who cites it
65 citing papers in PubMed, 93 citations in OpenAlex.
- Protein arginine methyltransferases coordinate mitochondrial stress adaptation and neuromuscular function.Experimental & molecular medicine · 2026Review
- Axonal Eif5a hypusination controls local translation and mitigates defects in FUS-ALS.Nature neuroscience · 2026Article
- Synaptic Vesicle Exocytosis and Endocytosis in Motor Nerve Endings of Transgenic Mice Modeling Amyotrophic Lateral Sclerosis upon Antioxidant Treatment and Gene-Cell Therapy.Doklady biological sciences : proceedings of the Academy of Sciences of the USSR, Biological sciences sections · 2025Article
- Brain Metabolic Features of FUS-ALS: A 2-[Annals of neurology · 2025Article
- Using ALS to understand profilin 1's diverse roles in cellular physiology.Cytoskeleton (Hoboken, N.J.) · 2025Review
- Muscle-specific kinase levels in blood are an early diagnostic biomarker for SOD1-93A mouse model of ALS.Frontiers in neurology · 2025Article
- Axonopathy Underlying Amyotrophic Lateral Sclerosis: Unraveling Complex Pathways and Therapeutic Insights.Neuroscience bulletin · 2024Review
- Endocytosis of Synaptic Vesicle in Motor Nerve Endings of FUS Transgenic Mice with a Model of Amyotrophic Lateral Sclerosis.Bulletin of experimental biology and medicine · 2024Article
- Resveratrol and Vitamin D: Eclectic Molecules Promoting Mitochondrial Health in Sarcopenia.International journal of molecular sciences · 2024Review
- Synaptopathy: presynaptic convergence in frontotemporal dementia and amyotrophic lateral sclerosis.Brain : a journal of neurology · 2024Review
- Exploring the Role of Metabolic Hormones in Amyotrophic Lateral Sclerosis.International journal of molecular sciences · 2024Article
- Mitochondria: A Promising Convergent Target for the Treatment of Amyotrophic Lateral Sclerosis.Cells · 2024Review
- Review
- Unraveling the causes of sarcopenia: Roles of neuromuscular junction impairment and mitochondrial dysfunction.Physiological reports · 2024Review
- NOX-induced oxidative stress is a primary trigger of major neurodegenerative disorders.Progress in neurobiology · 2023Review
- Mitochondrial Dyshomeostasis as an Early Hallmark and a Therapeutic Target in Amyotrophic Lateral Sclerosis.International journal of molecular sciences · 2023Review
- Review
- In-depth proteome analysis of brain tissue from Ewsr1 knockout mouse by multiplexed isobaric tandem mass tag labeling.Scientific reports · 2023Article
- Looking for answers far away from the soma-the (un)known axonal functions of TDP-43, and their contribution to early NMJ disruption in ALS.Molecular neurodegeneration · 2023Review
- Article
5 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
FUS (fused in sarcoma) mislocalization and cytoplasmic aggregation are hallmark pathologies in FUS-related amyotrophic lateral sclerosis and frontotemporal dementia. Many of the mechanistic hypotheses have focused on a loss of nuclear function in the FUS-opathies, implicating dysregulated RNA transcription and splicing in driving neurodegeneration. Recent studies describe an additional somato-dendritic localization for FUS in the cerebral cortex implying a regulatory role in mRNA transport and local translation at the synapse. Here, we report that FUS is also abundant at the pre-synaptic terminal of the neuromuscular junction (NMJ), suggesting an important function for this protein at peripheral synapses. We have previously reported dose and age-dependent motor neuron degeneration in transgenic mice overexpressing human wild-type FUS, resulting in a motor phenotype detected by ∼28 days and death by ∼100 days. Now, we report the earliest structural events using electron microscopy and quantitative immunohistochemistry. Mitochondrial abnormalities in the pre-synaptic motor nerve terminals are detected at postnatal day 6, which are more pronounced at P15 and accompanied by a loss of synaptic vesicles and synaptophysin protein coupled with NMJs of a smaller size at a time when there is no detectable motor neuron loss. These changes occur in the presence of abundant FUS and support a peripheral toxic gain of function. This appearance is typical of a 'dying-back' axonopathy, with the earliest manifestation being mitochondrial disruption. These findings support our hypothesis that FUS has an important function at the NMJ, and challenge the 'loss of nuclear function' hypothesis for disease pathogenesis in the FUS-opathies.
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