Protein misfolding and clearance in the pathogenesis of a new infantile onset ataxia caused by mutations in PRDX3
| العنوان: | Protein misfolding and clearance in the pathogenesis of a new infantile onset ataxia caused by mutations in PRDX3 |
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| المؤلفون: | Dolores Martínez-Rubio, Ángela Rodríguez-Prieto, Paula Sancho, Carmen Navarro-González, Nerea Gorría-Redondo, Javier Miquel-Leal, Clara Marco-Marín, Alison Jenkins, Mario Soriano-Navarro, Alberto Hernández, Belén Pérez-Dueñas, Pietro Fazzari, Sergio Aguilera-Albesa, Carmen Espinós |
| المساهمون: | Instituto de Salud Carlos III, European Commission, Ministerio de Economía y Competitividad (España), Fundació La Marató de TV3, Generalitat Valenciana, Ministerio de Ciencia e Innovación (España), Marco-Marín, Clara, Institut Català de la Salut, [Martínez-Rubio D] Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain. Joint Unit CIPF-IIS La Fe Rare Diseases, Valencia, Spain. [Rodríguez-Prieto Á, Navarro-González C, Miquel-Leal J] Cortical Circuits in Health and Disease Laboratory, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain. [Sancho P] Rare Neurodegenerative Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain. [Gorría-Redondo N] Pediatric Neurology Unit, Department of Pediatrics, Complejo Hospitalario de Navarra, Navarrabiomed, Pamplona, Spain. [Pérez-Dueñas B] Servei de Neurologia Pediàtrica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus |
| المصدر: | HUMAN MOLECULAR GENETICS r-CIPF. Repositorio Institucional Producción Científica del Centro de Investigación Principe Felipe (CIPF) instname r-IIS La Fe. Repositorio Institucional de Producción Científica del Instituto de Investigación Sanitaria La Fe Scientia |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Pediatria, Peroxiredoxin III, Cerebel - Degeneració, Cerebellar Ataxia, Otros calificadores::Otros calificadores::/genética [Otros calificadores], aminoácidos, péptidos y proteínas::proteínas::proteínas mitocondriales [COMPUESTOS QUÍMICOS Y DROGAS], General Medicine, Atàxia - Aspectes genètics, Mitochondrial Proteins, Mice, enfermedades del sistema nervioso::enfermedades del sistema nervioso central::enfermedades cerebrales::enfermedades cerebelosas::degeneraciones espinocerebelosas [ENFERMEDADES], enfermedades del sistema nervioso::manifestaciones neurológicas::discinesias::ataxia [ENFERMEDADES], Amino Acids, Peptides, and Proteins::Proteins::Mitochondrial Proteins [CHEMICALS AND DRUGS], Mutation, Other subheadings::Other subheadings::/genetics [Other subheadings], Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Cerebellar Diseases::Spinocerebellar Degenerations [DISEASES], Genetics, Humans, Animals, Ataxia, Molecular Biology, Genetics (clinical), Nervous System Diseases::Neurologic Manifestations::Dyskinesias::Ataxia [DISEASES], HeLa Cells, Spinocerebellar Degenerations |
| الوصف: | 17 páginas, 8 figuras Peroxiredoxin 3 (PRDX3) encodes a mitochondrial antioxidant protein, which is essential for the control of reactive oxygen species homeostasis. So far, PRDX3 mutations are involved in mild-to-moderate progressive juvenile onset cerebellar ataxia. We aimed to unravel the molecular bases underlying the disease in an infant suffering from cerebellar ataxia that started at 19 months old and presented severe cerebellar atrophy and peripheral neuropathy early in the course of disease. By whole exome sequencing, we identified a novel homozygous mutation, PRDX3 p.D163E, which impaired the mitochondrial ROS defense system. In mouse primary cortical neurons, the exogenous expression of PRDX3 p.D163E was reduced and triggered alterations in neurite morphology and in mitochondria. Mitochondrial computational parameters showed that p.D163E led to serious mitochondrial alterations. In transfected HeLa cells expressing the mutation, mitochondria accumulation was detected by correlative light electron microscopy. Mitochondrial morphology showed severe changes, including extremely damaged outer and inner membranes with a notable cristae disorganization. Moreover, spherical structures compatible with lipid droplets were identified, which can be associated with a generalized response to stress and can be involved in the removal of unfolded proteins. In the patient's fibroblasts, PRDX3 expression was nearly absent. The biochemical analysis suggested that the mutation p.D163E would result in an unstable structure tending to form aggregates that trigger unfolded protein responses via mitochondria and endoplasmic reticulum. Altogether, our findings broaden the clinical spectrum of the recently described PRDX3-associated neurodegeneration and provide new insight into the pathological mechanisms underlying this new form of cerebellar ataxia. The Instituto de Salud Carlos III (ISCIII)—Subdirección General de Evaluación y Fomento de la Investigación within the framework of the National R + D + I Plan cofunded with European Regional Development Funds (ERDF) (grants PI18/00147 and PI21/00103 to C.E.); the Spanish Ministry of Economy and Competitiveness (grant SAF2017-89020-R to P.F.); the Fundació La Marató TV3 (grants 20143130 and 20143131 to B.P.-D. and C.E.) and the Generalitat Valenciana (grant PROMETEO/2018/135 to C.E.). Part of the equipment employed in this work was funded by Generalitat Valenciana and co-financed with ERDF (OP ERDF of Comunitat Valenciana 2014-2020). P.F. and A.R.-P. are supported by the Spanish Ministry of Science and Innovation (grants RyC-2014-16410 to P.F. and PRE2018-083562 to A.R.-P.). |
| وصف الملف: | application/pdf |
| تدمد: | 1460-2083 0964-6906 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3cdcc3ce146164c11fcb0a4936001ae4Test https://pubmed.ncbi.nlm.nih.gov/35766882Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....3cdcc3ce146164c11fcb0a4936001ae4 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602083 09646906 |
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