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Amyotrophic Lateral Sclerosis, FUS and Protein Synthesis Defects

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Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that mainly affects the motor system. It is a very heterogeneous disorder, so far more than 40 genes have been described as responsible for ALS. The cause of motor neuron degeneration is not yet fully understood, but there is consensus in the literature that it is the result of a complex interplay of several pathogenic processes, which include alterations in nucleocytoplasmic transport, defects in transcription and splicing, altered formation and/or disassembly of stress granules and impaired proteostasis. These defects result in protein aggregation, impaired DNA repair, mitochondrial dysfunction and oxidative stress, neuroinflammation, impaired axonal transport, impaired vesicular transport, excitotoxicity, as well as impaired calcium influx. We argue here that all the above functions ultimately lead to defects in protein synthesis. Fused in Sarcoma (FUS) is one of the genes associated with ALS. It causes ALS type 6 when mutated and is found mislocalized to the cytoplasm in the motor neurons of sporadic ALS patients (without FUS mutations). In addition, FUS plays a role in all cellular functions that are impaired in degenerating motor neurons. Moreover, ALS patients with FUS mutations present the first symptoms significantly earlier than in other forms of the disease. Therefore, the aim of this review is to further discuss ALS6, detail the cellular functions of FUS, and suggest that the localization of FUS, as well as protein synthesis rates, could be hallmarks of the ALS phenotype and thus good therapeutic targets.

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Acknowledgements

We thank the people in the Foijer and Zatz labs for fruitful discussions.

Funding

This work was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and an Abel Tasman fellowship to AA awarded by the University of Groningen. The funding agencies had no role in the design of the study and collection, analysis, and interpretation of data or in writing the manuscript.

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Authors and Affiliations

  1. Human Genome and Stem Cell Research Center, Institute of Biosciences, University of São Paulo, 055080-090, CidadeUniversitária, São Paulo, Brazil

    Amanda Faria Assoni & Mayana Zatz

  2. European Research Institute for the Biology of Ageing, University of Groningen, 9713 AV, Groningen, The Netherlands

    Amanda Faria Assoni & Floris Foijer

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  1. Amanda Faria Assoni
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Contributions

Amanda F. Assoni: Conceptualization; literature search; data curation; writing – original draft; writing – review and editing. Floris Foijer: Conceptualization; resources; data curation; writing – review and editing. Mayana Zatz: Conceptualization; supervision; resources; writing – review and editing.

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Correspondence to Mayana Zatz.

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Assoni, A.F., Foijer, F. & Zatz, M. Amyotrophic Lateral Sclerosis, FUS and Protein Synthesis Defects. Stem Cell Rev and Rep 19, 625–638 (2023). https://doi.org/10.1007/s12015-022-10489-8

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