Background: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease, and protein aggregation has been proposed as a possible pathogenetic mechanism. However, the aggregate protein constituents are poorly characterized so knowledge on the role of aggregation in pathogenesis is limited. Methodology/Principal findings: We carried out a proteomic analysis of the protein composition of the insoluble fraction, as a model of protein aggregates, from familial ALS (fALS) mouse model at different disease stages. We identified several proteins enriched in the detergent-insoluble fraction already at a preclinical stage, including intermediate filaments, chaperones and mitochondrial proteins. Aconitase, HSC70 and cyclophilin A were also significantly enriched in the insoluble fraction of spinal cords of ALS patients. Moreover, we found that the majority of proteins in mice and HSP90 in patients were tyrosine-nitrated. We therefore investigated the role of nitrative stress in aggregate formation in fALS-like murine motor neuron-neuroblastoma (NSC-34) cell lines. By inhibiting nitric oxide synthesis the amount of insoluble proteins, particularly aconitase, HSC70, cyclophilin A and SOD1 can be substantially reduced. Conclusion/Significance: Analysis of the insoluble fractions from cellular/mouse models and human tissues revealed novel aggregation-prone proteins and suggests that nitrative stress contribute to protein aggregate formation in ALS.

Characterization of detergent-insoluble proteins in ALS indicates a causal link between nitrative stress and aggregation in pathogenesis / Basso, M; Samengo, G; Nardo, G; Massignan, T; D'Alessandro, Giuseppina; Tartari, S; Cantoni, L; Marino, M; Cheroni, C; DE BIASI, S; Giordana, Mt; Strong, Mj; Estevez, Ag; Salmona, M; Bendotti, C; Bonetto, V.. - In: PLOS ONE. - ISSN 1932-6203. - 4:12(2009). [10.1371/journal.pone.0008130]

Characterization of detergent-insoluble proteins in ALS indicates a causal link between nitrative stress and aggregation in pathogenesis

D'ALESSANDRO, GIUSEPPINA;
2009

Abstract

Background: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease, and protein aggregation has been proposed as a possible pathogenetic mechanism. However, the aggregate protein constituents are poorly characterized so knowledge on the role of aggregation in pathogenesis is limited. Methodology/Principal findings: We carried out a proteomic analysis of the protein composition of the insoluble fraction, as a model of protein aggregates, from familial ALS (fALS) mouse model at different disease stages. We identified several proteins enriched in the detergent-insoluble fraction already at a preclinical stage, including intermediate filaments, chaperones and mitochondrial proteins. Aconitase, HSC70 and cyclophilin A were also significantly enriched in the insoluble fraction of spinal cords of ALS patients. Moreover, we found that the majority of proteins in mice and HSP90 in patients were tyrosine-nitrated. We therefore investigated the role of nitrative stress in aggregate formation in fALS-like murine motor neuron-neuroblastoma (NSC-34) cell lines. By inhibiting nitric oxide synthesis the amount of insoluble proteins, particularly aconitase, HSC70, cyclophilin A and SOD1 can be substantially reduced. Conclusion/Significance: Analysis of the insoluble fractions from cellular/mouse models and human tissues revealed novel aggregation-prone proteins and suggests that nitrative stress contribute to protein aggregate formation in ALS.
protein aggregates; nitrative stress; ALS
01 Pubblicazione su rivista::01a Articolo in rivista
Characterization of detergent-insoluble proteins in ALS indicates a causal link between nitrative stress and aggregation in pathogenesis / Basso, M; Samengo, G; Nardo, G; Massignan, T; D'Alessandro, Giuseppina; Tartari, S; Cantoni, L; Marino, M; Cheroni, C; DE BIASI, S; Giordana, Mt; Strong, Mj; Estevez, Ag; Salmona, M; Bendotti, C; Bonetto, V.. - In: PLOS ONE. - ISSN 1932-6203. - 4:12(2009). [10.1371/journal.pone.0008130]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/345952
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