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.

Proteomics analysis of FUS mutant human motoneurons reveals altered regulation of cytoskeleton and other ALS-linked proteins via 3′UTR binding / Garone, Maria Giovanna; Alfano, Vincenzo; Salvatori, Beatrice; Braccia, Clarissa; Peruzzi, Giovanna; Colantoni, Alessio; Bozzoni, Irene; Armirotti, Andrea; Rosa, Alessandro. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 10:1(2020). [10.1038/s41598-020-68794-6]

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

Garone, Maria Giovanna
Co-primo
;
Alfano, Vincenzo
Co-primo
;
Salvatori, Beatrice;Peruzzi, Giovanna;Colantoni, Alessio;Bozzoni, Irene;Rosa, Alessandro
Ultimo
2020

Abstract

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.
2020
FUS; iPSC; motoneuron; mass-spectrometry; cytoskeleton; oxidation-reduction; VCP; ASAP1; 3’UTR
01 Pubblicazione su rivista::01a Articolo in rivista
Proteomics analysis of FUS mutant human motoneurons reveals altered regulation of cytoskeleton and other ALS-linked proteins via 3′UTR binding / Garone, Maria Giovanna; Alfano, Vincenzo; Salvatori, Beatrice; Braccia, Clarissa; Peruzzi, Giovanna; Colantoni, Alessio; Bozzoni, Irene; Armirotti, Andrea; Rosa, Alessandro. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 10:1(2020). [10.1038/s41598-020-68794-6]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1430664
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