Differential Protein Expression in Extracellular Vesicles Defines Treatment Responders and Non-Responders in Multiple Sclerosis.
Gabriel Torres Iglesias, MariPaz López-Molina, Lucía Botella, Fernando Laso-García, Beatriz Chamorro, Mireya Fernández-Fournier, Inmaculada Puertas, Susana B Bravo, Elisa Alonso-López, Exuperio Díez-Tejedor, María Gutiérrez-Fernández, Laura Otero-Ortega
Author Information
Gabriel Torres Iglesias: Neurological Sciences and Cerebrovascular Research Laboratory, Department of Neurology, Neurology and Cerebrovascular Disease Group, Neuroscience Area of Hospital La Paz Institute for Health Research-IdiPAZ (La Paz University Hospital-Universidad Autónoma de Madrid), 28046 Madrid, Spain.
MariPaz López-Molina: Neurological Sciences and Cerebrovascular Research Laboratory, Department of Neurology, Neurology and Cerebrovascular Disease Group, Neuroscience Area of Hospital La Paz Institute for Health Research-IdiPAZ (La Paz University Hospital-Universidad Autónoma de Madrid), 28046 Madrid, Spain.
Lucía Botella: Neurological Sciences and Cerebrovascular Research Laboratory, Department of Neurology, Neurology and Cerebrovascular Disease Group, Neuroscience Area of Hospital La Paz Institute for Health Research-IdiPAZ (La Paz University Hospital-Universidad Autónoma de Madrid), 28046 Madrid, Spain.
Fernando Laso-García: Neurological Sciences and Cerebrovascular Research Laboratory, Department of Neurology, Neurology and Cerebrovascular Disease Group, Neuroscience Area of Hospital La Paz Institute for Health Research-IdiPAZ (La Paz University Hospital-Universidad Autónoma de Madrid), 28046 Madrid, Spain.
Beatriz Chamorro: Neurological Sciences and Cerebrovascular Research Laboratory, Department of Neurology, Neurology and Cerebrovascular Disease Group, Neuroscience Area of Hospital La Paz Institute for Health Research-IdiPAZ (La Paz University Hospital-Universidad Autónoma de Madrid), 28046 Madrid, Spain.
Mireya Fernández-Fournier: Neurological Sciences and Cerebrovascular Research Laboratory, Department of Neurology, Neurology and Cerebrovascular Disease Group, Neuroscience Area of Hospital La Paz Institute for Health Research-IdiPAZ (La Paz University Hospital-Universidad Autónoma de Madrid), 28046 Madrid, Spain. ORCID
Inmaculada Puertas: Neurological Sciences and Cerebrovascular Research Laboratory, Department of Neurology, Neurology and Cerebrovascular Disease Group, Neuroscience Area of Hospital La Paz Institute for Health Research-IdiPAZ (La Paz University Hospital-Universidad Autónoma de Madrid), 28046 Madrid, Spain.
Susana B Bravo: Proteomics Unit, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain. ORCID
Elisa Alonso-López: Neurological Sciences and Cerebrovascular Research Laboratory, Department of Neurology, Neurology and Cerebrovascular Disease Group, Neuroscience Area of Hospital La Paz Institute for Health Research-IdiPAZ (La Paz University Hospital-Universidad Autónoma de Madrid), 28046 Madrid, Spain. ORCID
Exuperio Díez-Tejedor: Neurological Sciences and Cerebrovascular Research Laboratory, Department of Neurology, Neurology and Cerebrovascular Disease Group, Neuroscience Area of Hospital La Paz Institute for Health Research-IdiPAZ (La Paz University Hospital-Universidad Autónoma de Madrid), 28046 Madrid, Spain.
María Gutiérrez-Fernández: Neurological Sciences and Cerebrovascular Research Laboratory, Department of Neurology, Neurology and Cerebrovascular Disease Group, Neuroscience Area of Hospital La Paz Institute for Health Research-IdiPAZ (La Paz University Hospital-Universidad Autónoma de Madrid), 28046 Madrid, Spain.
Laura Otero-Ortega: Neurological Sciences and Cerebrovascular Research Laboratory, Department of Neurology, Neurology and Cerebrovascular Disease Group, Neuroscience Area of Hospital La Paz Institute for Health Research-IdiPAZ (La Paz University Hospital-Universidad Autónoma de Madrid), 28046 Madrid, Spain. ORCID
Multiple sclerosis (MS) remains the leading cause of neurological disability among young adults worldwide, underscoring the urgent need to define the best therapeutic strategy. Recent advances in proteomics have deepened our understanding of treatment mechanisms and revealed promising biomarkers for predicting therapeutic outcomes. This study focuses on the identification of a protein profile of circulating extracellular vesicles (EVs) derived from neurons, oligodendrocytes, and B and T cells able to differentiate treatment responders and non-responders in 80 patients with MS. In the patients who responded to treatment, T cell-derived EVs were enriched in LV151, a protein involved in the promotion of anti-inflammatory cytokines, whereas Bcell-derived EVs showed elevated PSMD6 and PTPRC, related to immunoproteasome function. Oligodendrocyte- and neuron-derived EVs showed upregulated CO6A1 and COEA1, involved in extracellular matrix reorganisation, as well as LAMA5, NonO, SPNT, and NCAM, which are critical for brain repair. In contrast, non-responders showed higher levels of PSMD7 and PRS10 from B cell-derived EVs, associated with DNA damage, and increased levels of PERM and PERL from T cell-derived EVs, linked to nuclear factor kappa B activation and drug-resistant proteins such as HS90A and RASK. These findings highlight a distinct panel of proteins in EVs that could serve as an early indicator of treatment efficacy in MS.
