Quantitative Changes in the Mitochondrial Proteome of Cerebellar Synaptosomes From Preclinical Cystatin B-Deficient Mice
Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1) is a neurodegenerative disorder caused by loss-of-function mutations in the cystatin B (CSTB) gene. Progression of the clinical symptoms in EPM1 patients, including stimulus-sensitive myoclonus, tonic-clonic seizures, and ataxia, are...
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Frontiers Media S.A.
2020-11-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2020.570640/full |
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| author | Katarin Gorski Katarin Gorski Albert Spoljaric Tuula A. Nyman Kai Kaila Brendan J. Battersby Anna-Elina Lehesjoki Anna-Elina Lehesjoki |
| author_facet | Katarin Gorski Katarin Gorski Albert Spoljaric Tuula A. Nyman Kai Kaila Brendan J. Battersby Anna-Elina Lehesjoki Anna-Elina Lehesjoki |
| author_sort | Katarin Gorski |
| collection | DOAJ |
| description | Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1) is a neurodegenerative disorder caused by loss-of-function mutations in the cystatin B (CSTB) gene. Progression of the clinical symptoms in EPM1 patients, including stimulus-sensitive myoclonus, tonic-clonic seizures, and ataxia, are well described. However, the cellular dysfunction during the presymptomatic phase that precedes the disease onset is not understood. CSTB deficiency leads to alterations in GABAergic signaling, and causes early neuroinflammation followed by progressive neurodegeneration in brains of a mouse model, manifesting as progressive myoclonus and ataxia. Here, we report the first proteome atlas from cerebellar synaptosomes of presymptomatic Cstb-deficient mice, and propose that early mitochondrial dysfunction is important to the pathogenesis of altered synaptic function in EPM1. A decreased sodium- and chloride dependent GABA transporter 1 (GAT-1) abundance was noted in synaptosomes with CSTB deficiency, but no functional difference was seen between the two genotypes in electrophysiological experiments with pharmacological block of GAT-1. Collectively, our findings provide novel insights into the early onset and pathogenesis of CSTB deficiency, and reveal greater complexity to the molecular pathogenesis of EPM1. |
| first_indexed | 2024-12-22T20:10:51Z |
| format | Article |
| id | doaj.art-f25b3b2f46794c56a9d29d0251530174 |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-12-22T20:10:51Z |
| publishDate | 2020-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-f25b3b2f46794c56a9d29d02515301742022-12-21T18:14:03ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992020-11-011310.3389/fnmol.2020.570640570640Quantitative Changes in the Mitochondrial Proteome of Cerebellar Synaptosomes From Preclinical Cystatin B-Deficient MiceKatarin Gorski0Katarin Gorski1Albert Spoljaric2Tuula A. Nyman3Kai Kaila4Brendan J. Battersby5Anna-Elina Lehesjoki6Anna-Elina Lehesjoki7Folkhälsan Research Center, Helsinki, FinlandDepartment of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, FinlandMolecular and Integrative Biosciences, and Neuroscience Center (HiLIFE), Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, FinlandInstitute of Clinical Medicine, University of Oslo and Oslo University Hospital, Oslo, NorwayMolecular and Integrative Biosciences, and Neuroscience Center (HiLIFE), Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, FinlandInstitute of Biotechnology, University of Helsinki, Helsinki, FinlandFolkhälsan Research Center, Helsinki, FinlandDepartment of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, FinlandProgressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1) is a neurodegenerative disorder caused by loss-of-function mutations in the cystatin B (CSTB) gene. Progression of the clinical symptoms in EPM1 patients, including stimulus-sensitive myoclonus, tonic-clonic seizures, and ataxia, are well described. However, the cellular dysfunction during the presymptomatic phase that precedes the disease onset is not understood. CSTB deficiency leads to alterations in GABAergic signaling, and causes early neuroinflammation followed by progressive neurodegeneration in brains of a mouse model, manifesting as progressive myoclonus and ataxia. Here, we report the first proteome atlas from cerebellar synaptosomes of presymptomatic Cstb-deficient mice, and propose that early mitochondrial dysfunction is important to the pathogenesis of altered synaptic function in EPM1. A decreased sodium- and chloride dependent GABA transporter 1 (GAT-1) abundance was noted in synaptosomes with CSTB deficiency, but no functional difference was seen between the two genotypes in electrophysiological experiments with pharmacological block of GAT-1. Collectively, our findings provide novel insights into the early onset and pathogenesis of CSTB deficiency, and reveal greater complexity to the molecular pathogenesis of EPM1.https://www.frontiersin.org/articles/10.3389/fnmol.2020.570640/fullmyoclonus epilepsysynaptosomeneurodegenerationcerebellaelectrophysiologymitochondria |
| spellingShingle | Katarin Gorski Katarin Gorski Albert Spoljaric Tuula A. Nyman Kai Kaila Brendan J. Battersby Anna-Elina Lehesjoki Anna-Elina Lehesjoki Quantitative Changes in the Mitochondrial Proteome of Cerebellar Synaptosomes From Preclinical Cystatin B-Deficient Mice Frontiers in Molecular Neuroscience myoclonus epilepsy synaptosome neurodegeneration cerebella electrophysiology mitochondria |
| title | Quantitative Changes in the Mitochondrial Proteome of Cerebellar Synaptosomes From Preclinical Cystatin B-Deficient Mice |
| title_full | Quantitative Changes in the Mitochondrial Proteome of Cerebellar Synaptosomes From Preclinical Cystatin B-Deficient Mice |
| title_fullStr | Quantitative Changes in the Mitochondrial Proteome of Cerebellar Synaptosomes From Preclinical Cystatin B-Deficient Mice |
| title_full_unstemmed | Quantitative Changes in the Mitochondrial Proteome of Cerebellar Synaptosomes From Preclinical Cystatin B-Deficient Mice |
| title_short | Quantitative Changes in the Mitochondrial Proteome of Cerebellar Synaptosomes From Preclinical Cystatin B-Deficient Mice |
| title_sort | quantitative changes in the mitochondrial proteome of cerebellar synaptosomes from preclinical cystatin b deficient mice |
| topic | myoclonus epilepsy synaptosome neurodegeneration cerebella electrophysiology mitochondria |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2020.570640/full |
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