Dataset Information

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

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.

SUBMITTER: Basso M

PROVIDER: S-EPMC2780298 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Publications

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

Basso Manuela M Samengo Giuseppina G Nardo Giovanni G Massignan Tania T D'Alessandro Giuseppina G Tartari Silvia S Cantoni Lavinia L Marino Marianna M Cheroni Cristina C De Biasi Silvia S Giordana Maria Teresa MT Strong Michael J MJ Estevez Alvaro G AG Salmona Mario M Bendotti Caterina C Bonetto Valentina V

PloS one 20091202 12

<h4>Background</h4>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.<h4>Methodology/principal findings</h4>We carried out a proteomic analysis of the protein composition of the insoluble fraction, as a model of protein aggregates, from familial ALS ...[more]

PMID: 19956584

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Project description:Neurodegenerative diseases are often defined pathologically by the presence of protein aggregates. These aggregates, including amyloid plaques in Alzheimer's disease (AD), result from the abnormal accumulation and processing of proteins, and may ultimately lead to neuronal dysfunction and cell death. To date, conventional biochemical studies have revealed abundant core components in protein aggregates. However, rapidly improving proteomics technologies offer opportunities to revisit pathologic aggregate composition, and to identify less abundant but potentially important functional molecules that participate in neurodegeneration. The purpose of this study was to establish a proteomic strategy for the profiling of neurodegenerative disease tissues for disease-specific changes in protein abundance. Using high resolution liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS), we analyzed detergent-insoluble frontal cortex samples from AD and unaffected control cases. In addition, we analyzed samples from frontotemporal lobar degeneration (FTLD) cases to identify AD-specific changes not present in other neurodegenerative diseases. We used a labeling-free quantification technique to compare the abundance of identified peptides in the samples based on extracted ion current (XIC) of their corresponding ions. Of the 512 identified proteins, quantitation demonstrated significant changes in 81 AD-specific proteins. Following additional manual filtering, 11 proteins were accepted with high confidence as increased in AD compared to control and FTLD brains, including beta-amyloid, tau and apolipoprotein E, all well-established AD-linked proteins. In addition, we identified and validated the presence of serine protease 15, ankyrin B, and 14-3-3 eta in the detergent-insoluble fraction. Our results provide further evidence for the capacity of proteomics applications to identify conserved sets of disease-specific proteins in AD, to enhance our understanding of disease pathogenesis, and to deliver new candidates for the development of effective therapies for this, and other, devastating neurodegenerative disorders.

Dataset Information

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

Background

Methodology/principal findings

Conclusion/significance

Publications

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

Similar Datasets

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