Mukesh Gautam, Ali Laith, Aslihan Gunel, Melda Yilmaz, Nazli Basak, Halil Idrisoglu, P Hande Ozdinler
{"title":"SOD1D90A突变外泌体蛋白质组学提示疾病早期机制,FN1可作为生物标志物","authors":"Mukesh Gautam, Ali Laith, Aslihan Gunel, Melda Yilmaz, Nazli Basak, Halil Idrisoglu, P Hande Ozdinler","doi":"10.1002/acn3.70208","DOIUrl":null,"url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease. Super oxide dismutase 1 (SOD1) gene mutations cause ALS, and the D90A mutation is associated with primarily upper motor neuron (UMN) loss.</p><p><strong>Objective: </strong>Our goal is to reveal the early cellular events in ALS pathology and identify potential pharmacokinetic biomarkers, using well-defined patient populations.</p><p><strong>Methods: </strong>Exosomes are isolated from serum either single or multiple time points from members of one family, who have SOD1<sup>D90A</sup> mutation, and their protein content is assessed by tandem mass-spec proteomics. Ingenuity Pathway analysis is used to highlight cellular events that are perturbed as the disease progressed. The linear regression analysis, using ALSFRS scores of patients and the protein content, helps identify potential pharmacokinetic biomarkers, which are confirmed with the ELISA assay.</p><p><strong>Results: </strong>Father, Son, and Daughter are at different disease stages and carry the SOD1<sup>D90A</sup> mutation. Albeit, the Daughter remained asymptomatic within a year; she had significant biological changes. The Son transitioned from asymptomatic to early symptomatic within a year, while the Father was symptomatic. Patient #2, who also had the SOD1<sup>D90A</sup> mutation, was more advanced. Comparison of the Son, Father, and Patient #2 suggested Fibronectin1 (FN1) as a potential pharmacokinetic biomarker, which is confirmed by ELISA.</p><p><strong>Interpretation: </strong>Exosome proteomics offer a powerful approach to interrogate disease-specific or disease-related proteins that become present in the blood. This helps define the perturbed cellular events with respect to disease progression and reveal potential pharmacokinetic biomarkers. We find FN1 levels to increase with disease progression, suggesting it may be a pharmacokinetic biomarker, especially for ALS patients with prominent UMN loss.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9000,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Exosome Proteomics of SOD1<sup>D90A</sup> Mutation Suggest Early Disease Mechanisms, and FN1 as a Biomarker.\",\"authors\":\"Mukesh Gautam, Ali Laith, Aslihan Gunel, Melda Yilmaz, Nazli Basak, Halil Idrisoglu, P Hande Ozdinler\",\"doi\":\"10.1002/acn3.70208\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease. Super oxide dismutase 1 (SOD1) gene mutations cause ALS, and the D90A mutation is associated with primarily upper motor neuron (UMN) loss.</p><p><strong>Objective: </strong>Our goal is to reveal the early cellular events in ALS pathology and identify potential pharmacokinetic biomarkers, using well-defined patient populations.</p><p><strong>Methods: </strong>Exosomes are isolated from serum either single or multiple time points from members of one family, who have SOD1<sup>D90A</sup> mutation, and their protein content is assessed by tandem mass-spec proteomics. Ingenuity Pathway analysis is used to highlight cellular events that are perturbed as the disease progressed. The linear regression analysis, using ALSFRS scores of patients and the protein content, helps identify potential pharmacokinetic biomarkers, which are confirmed with the ELISA assay.</p><p><strong>Results: </strong>Father, Son, and Daughter are at different disease stages and carry the SOD1<sup>D90A</sup> mutation. Albeit, the Daughter remained asymptomatic within a year; she had significant biological changes. The Son transitioned from asymptomatic to early symptomatic within a year, while the Father was symptomatic. Patient #2, who also had the SOD1<sup>D90A</sup> mutation, was more advanced. Comparison of the Son, Father, and Patient #2 suggested Fibronectin1 (FN1) as a potential pharmacokinetic biomarker, which is confirmed by ELISA.</p><p><strong>Interpretation: </strong>Exosome proteomics offer a powerful approach to interrogate disease-specific or disease-related proteins that become present in the blood. This helps define the perturbed cellular events with respect to disease progression and reveal potential pharmacokinetic biomarkers. We find FN1 levels to increase with disease progression, suggesting it may be a pharmacokinetic biomarker, especially for ALS patients with prominent UMN loss.</p>\",\"PeriodicalId\":126,\"journal\":{\"name\":\"Annals of Clinical and Translational Neurology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.9000,\"publicationDate\":\"2025-09-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Annals of Clinical and Translational Neurology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1002/acn3.70208\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Annals of Clinical and Translational Neurology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/acn3.70208","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
Exosome Proteomics of SOD1D90A Mutation Suggest Early Disease Mechanisms, and FN1 as a Biomarker.
Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease. Super oxide dismutase 1 (SOD1) gene mutations cause ALS, and the D90A mutation is associated with primarily upper motor neuron (UMN) loss.
Objective: Our goal is to reveal the early cellular events in ALS pathology and identify potential pharmacokinetic biomarkers, using well-defined patient populations.
Methods: Exosomes are isolated from serum either single or multiple time points from members of one family, who have SOD1D90A mutation, and their protein content is assessed by tandem mass-spec proteomics. Ingenuity Pathway analysis is used to highlight cellular events that are perturbed as the disease progressed. The linear regression analysis, using ALSFRS scores of patients and the protein content, helps identify potential pharmacokinetic biomarkers, which are confirmed with the ELISA assay.
Results: Father, Son, and Daughter are at different disease stages and carry the SOD1D90A mutation. Albeit, the Daughter remained asymptomatic within a year; she had significant biological changes. The Son transitioned from asymptomatic to early symptomatic within a year, while the Father was symptomatic. Patient #2, who also had the SOD1D90A mutation, was more advanced. Comparison of the Son, Father, and Patient #2 suggested Fibronectin1 (FN1) as a potential pharmacokinetic biomarker, which is confirmed by ELISA.
Interpretation: Exosome proteomics offer a powerful approach to interrogate disease-specific or disease-related proteins that become present in the blood. This helps define the perturbed cellular events with respect to disease progression and reveal potential pharmacokinetic biomarkers. We find FN1 levels to increase with disease progression, suggesting it may be a pharmacokinetic biomarker, especially for ALS patients with prominent UMN loss.
期刊介绍:
Annals of Clinical and Translational Neurology is a peer-reviewed journal for rapid dissemination of high-quality research related to all areas of neurology. The journal publishes original research and scholarly reviews focused on the mechanisms and treatments of diseases of the nervous system; high-impact topics in neurologic education; and other topics of interest to the clinical neuroscience community.