Phenotypes and malignancy risk of different <i>FUS</i> mutations in genetic amyotrophic lateral sclerosis

Naumann, Marcel; Peikert, Kevin; Günther, René; Kooi, Anneke J. van der; Aronica, Eleonora; Hübers, Annemarie; Danel, Véronique; Corcia, Philippe; Pan‐Montojo, Francisco; Çırak, Sebahattin; Haliloğlu, Göknur; Ludolph, Albert C.; Goswami, Anand; Andersen, Peter M.; Prudlo, Johannes; Wegner, Florian; Damme, Philip Van; Weishaupt, Jochen H.; Hermann, Andreas

doi:10.1002/acn3.50930

Cited by 55 publications

(46 citation statements)

References 30 publications

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“…In this work we took advantage of pure populations of hiPSC-derived motoneurons to study the impact of a FUS mutation, linked to severe and juvenile ALS 15 , on the human motoneuron proteome. Interestingly, GO term enrichment analysis suggested that proteins involved in catabolic processes and oxidation-reduction are upregulated in FUS mutant cells.…”

Section: Discussionmentioning

confidence: 99%

Proteomics analysis of FUS mutant human motoneurons reveals altered regulation of cytoskeleton and other ALS-linked proteins via 3′UTR binding

Garone

Alfano

Salvatori

et al. 2020

Sci Rep

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increasing evidence suggests that in Amyotrophic Lateral Sclerosis (ALS) mutated RnA binding proteins acquire aberrant functions, leading to altered RNA metabolism with significant impact on encoded protein levels. Here, by taking advantage of a human induced pluripotent stem cell-based model, we aimed to gain insights on the impact of ALS mutant fUS on the motoneuron proteome. Label-free proteomics analysis by mass-spectrometry revealed upregulation of proteins involved in catabolic processes and oxidation-reduction, and downregulation of cytoskeletal proteins and factors directing neuron projection. Mechanistically, proteome alteration does not correlate with transcriptome changes. Rather, we observed a strong correlation with selective binding of mutant fUS to target mRNAs in their 3′UtR. novel validated targets, selectively bound by mutant fUS, include genes previously involved in familial or sporadic ALS, such as VCP, and regulators of membrane trafficking and cytoskeleton remodeling, such as ASAP1. These findings unveil a novel mechanism by which mutant fUS might intersect other pathogenic pathways in ALS patients' motoneurons. The motoneuron disease Amyotrophic Lateral Sclerosis (ALS) has been linked to mutations in several RNA binding proteins (RBPs) and altered RNA metabolism 1,2. ALS mutations affecting nuclear localization of the RBP FUS are regarded as a primary event, eventually leading to motoneuron death by unknown mechanisms 3,4. Accordingly, FUS mutations that cause higher levels of mislocalization in the cytoplasm (such as the P525L) are associated to more aggressive and juvenile ALS pathology 5. However, little is known about the effects of abnormal FUS accumulation in the cytoplasm on its RNA targets. A change in the translatome has been previously observed in neurons derived from mouse embryonic stem cells ectopically overexpressing human FUS-R495X protein, which is another mutant FUS mislocalized to the cytoplasm 6. Alteration of protein translation was also studied upon oxidative stress and ectopic expression of wild-type (WT) or R495X mutant FUS in neuroblastoma cells 7. However, overexpression of WT FUS at non-physiological levels is known to produce toxic effects per se 8. Moreover, since ALS specifically affects motoneurons 9 , disease-relevant targets might be missed in in vitro models based on non-motoneuronal cells. The effect of mutant FUS on the proteome of human motoneurons remains unexplored.

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Section: Discussionmentioning

confidence: 99%

Proteomics analysis of FUS mutant human motoneurons reveals altered regulation of cytoskeleton and other ALS-linked proteins via 3′UTR binding

Garone

Alfano

Salvatori

et al. 2020

Sci Rep

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“…The clinical classification of ALS associated with FUS mutation has been designated as familial ALS type 6 (ALS6; Vance et al, 2009). Most patients with ALS6 appear to be predominantly lower motor neuron with young onset, aggressive course, high incidence of bulbar symptoms, and early respiratory involvement, although typical ALS phenotype and slower disease course have also been described in some patients (Naumann et al, 2020; Sproviero et al, 2012). FUS mutations have been reported to be responsible for 3%–4% of familial ALS and for less than 1% of sporadic ALS (Zou et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

FUS P525L mutation causing amyotrophic lateral sclerosis and movement disorders

et al. 2020

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“…They have been demonstrated to affect subcellular distribution or increase the propensity to form cytoplasmic FUS-positive granules [ 105 ], with effects going beyond an expected, albeit partial, loss of function. From a clinical point of view, these frameshift variants are frequently associated with a juvenile and rapidly progressive form of ALS [ 106 ]. A specific nonsense variant, c.868C > T (commonly referred to as p.Glu290 *), has been identified as the cause of essential tremor in a large family [ 107 ].…”

Section: Applying the Acmg Standards And Guidelines For The Interpmentioning

confidence: 99%

High-Throughput Genetic Testing in ALS: The Challenging Path of Variant Classification Considering the ACMG Guidelines

Lattante

Marangi

Doronzio

et al. 2020

Genes

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The development of high-throughput sequencing technologies and screening of big patient cohorts with familial and sporadic amyotrophic lateral sclerosis (ALS) led to the identification of a significant number of genetic variants, which are sometimes difficult to interpret. The American College of Medical Genetics and Genomics (ACMG) provided guidelines to help molecular geneticists and pathologists to interpret variants found in laboratory testing. We assessed the application of the ACMG criteria to ALS-related variants, combining data from literature with our experience. We analyzed a cohort of 498 ALS patients using massive parallel sequencing of ALS-associated genes and identified 280 variants with a minor allele frequency < 1%. Examining all variants using the ACMG criteria, thus considering the type of variant, inheritance, familial segregation, and possible functional studies, we classified 20 variants as “pathogenic”. In conclusion, ALS’s genetic complexity, such as oligogenic inheritance, presence of genes acting as risk factors, and reduced penetrance, needs to be considered when interpreting variants. The goal of this work is to provide helpful suggestions to geneticists and clinicians dealing with ALS.

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Phenotypes and malignancy risk of different FUS mutations in genetic amyotrophic lateral sclerosis

Cited by 55 publications

References 30 publications

Proteomics analysis of FUS mutant human motoneurons reveals altered regulation of cytoskeleton and other ALS-linked proteins via 3′UTR binding

Proteomics analysis of FUS mutant human motoneurons reveals altered regulation of cytoskeleton and other ALS-linked proteins via 3′UTR binding

FUS P525L mutation causing amyotrophic lateral sclerosis and movement disorders

High-Throughput Genetic Testing in ALS: The Challenging Path of Variant Classification Considering the ACMG Guidelines

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