Characterization of detergent-insoluble proteins in ALS indicates a causal link between nitrative stress and aggregation in pathogenesis.
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...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2009-12-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC2780298?pdf=render |
| _version_ | 1811226190681210880 |
|---|---|
| author | Manuela Basso Giuseppina Samengo Giovanni Nardo Tania Massignan Giuseppina D'Alessandro Silvia Tartari Lavinia Cantoni Marianna Marino Cristina Cheroni Silvia De Biasi Maria Teresa Giordana Michael J Strong Alvaro G Estevez Mario Salmona Caterina Bendotti Valentina Bonetto |
| author_facet | Manuela Basso Giuseppina Samengo Giovanni Nardo Tania Massignan Giuseppina D'Alessandro Silvia Tartari Lavinia Cantoni Marianna Marino Cristina Cheroni Silvia De Biasi Maria Teresa Giordana Michael J Strong Alvaro G Estevez Mario Salmona Caterina Bendotti Valentina Bonetto |
| author_sort | Manuela Basso |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T09:20:12Z |
| format | Article |
| id | doaj.art-3c2c108b06e54b4694839cae0d95622e |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T09:20:12Z |
| publishDate | 2009-12-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-3c2c108b06e54b4694839cae0d95622e2022-12-22T03:38:40ZengPublic Library of Science (PLoS)PLoS ONE1932-62032009-12-01412e813010.1371/journal.pone.0008130Characterization of detergent-insoluble proteins in ALS indicates a causal link between nitrative stress and aggregation in pathogenesis.Manuela BassoGiuseppina SamengoGiovanni NardoTania MassignanGiuseppina D'AlessandroSilvia TartariLavinia CantoniMarianna MarinoCristina CheroniSilvia De BiasiMaria Teresa GiordanaMichael J StrongAlvaro G EstevezMario SalmonaCaterina BendottiValentina BonettoBACKGROUND: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.http://europepmc.org/articles/PMC2780298?pdf=render |
| spellingShingle | Manuela Basso Giuseppina Samengo Giovanni Nardo Tania Massignan Giuseppina D'Alessandro Silvia Tartari Lavinia Cantoni Marianna Marino Cristina Cheroni Silvia De Biasi Maria Teresa Giordana Michael J Strong Alvaro G Estevez Mario Salmona Caterina Bendotti Valentina Bonetto Characterization of detergent-insoluble proteins in ALS indicates a causal link between nitrative stress and aggregation in pathogenesis. PLoS ONE |
| title | Characterization of detergent-insoluble proteins in ALS indicates a causal link between nitrative stress and aggregation in pathogenesis. |
| title_full | Characterization of detergent-insoluble proteins in ALS indicates a causal link between nitrative stress and aggregation in pathogenesis. |
| title_fullStr | Characterization of detergent-insoluble proteins in ALS indicates a causal link between nitrative stress and aggregation in pathogenesis. |
| title_full_unstemmed | Characterization of detergent-insoluble proteins in ALS indicates a causal link between nitrative stress and aggregation in pathogenesis. |
| title_short | Characterization of detergent-insoluble proteins in ALS indicates a causal link between nitrative stress and aggregation in pathogenesis. |
| title_sort | characterization of detergent insoluble proteins in als indicates a causal link between nitrative stress and aggregation in pathogenesis |
| url | http://europepmc.org/articles/PMC2780298?pdf=render |
| work_keys_str_mv | AT manuelabasso characterizationofdetergentinsolubleproteinsinalsindicatesacausallinkbetweennitrativestressandaggregationinpathogenesis AT giuseppinasamengo characterizationofdetergentinsolubleproteinsinalsindicatesacausallinkbetweennitrativestressandaggregationinpathogenesis AT giovanninardo characterizationofdetergentinsolubleproteinsinalsindicatesacausallinkbetweennitrativestressandaggregationinpathogenesis AT taniamassignan characterizationofdetergentinsolubleproteinsinalsindicatesacausallinkbetweennitrativestressandaggregationinpathogenesis AT giuseppinadalessandro characterizationofdetergentinsolubleproteinsinalsindicatesacausallinkbetweennitrativestressandaggregationinpathogenesis AT silviatartari characterizationofdetergentinsolubleproteinsinalsindicatesacausallinkbetweennitrativestressandaggregationinpathogenesis AT laviniacantoni characterizationofdetergentinsolubleproteinsinalsindicatesacausallinkbetweennitrativestressandaggregationinpathogenesis AT mariannamarino characterizationofdetergentinsolubleproteinsinalsindicatesacausallinkbetweennitrativestressandaggregationinpathogenesis AT cristinacheroni characterizationofdetergentinsolubleproteinsinalsindicatesacausallinkbetweennitrativestressandaggregationinpathogenesis AT silviadebiasi characterizationofdetergentinsolubleproteinsinalsindicatesacausallinkbetweennitrativestressandaggregationinpathogenesis AT mariateresagiordana characterizationofdetergentinsolubleproteinsinalsindicatesacausallinkbetweennitrativestressandaggregationinpathogenesis AT michaeljstrong characterizationofdetergentinsolubleproteinsinalsindicatesacausallinkbetweennitrativestressandaggregationinpathogenesis AT alvarogestevez characterizationofdetergentinsolubleproteinsinalsindicatesacausallinkbetweennitrativestressandaggregationinpathogenesis AT mariosalmona characterizationofdetergentinsolubleproteinsinalsindicatesacausallinkbetweennitrativestressandaggregationinpathogenesis AT caterinabendotti characterizationofdetergentinsolubleproteinsinalsindicatesacausallinkbetweennitrativestressandaggregationinpathogenesis AT valentinabonetto characterizationofdetergentinsolubleproteinsinalsindicatesacausallinkbetweennitrativestressandaggregationinpathogenesis |