Progressive mitochondrial dysfunction in cerebellar synaptosomes of cystatin B-deficient mice
The involvement of mitochondrial dysfunction in cystatin B (CSTB) deficiency has been suggested, but its role in the onset of neurodegeneration, myoclonus, and ataxia in the CSTB-deficient mouse model (Cstb−/−) is yet unknown. CSTB is an inhibitor of lysosomal and nuclear cysteine cathepsins. In hum...
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Frontiers Media S.A.
2023-05-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2023.1175851/full |
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| author | Katarin Gorski Katarin Gorski Christopher B. Jackson Tuula A. Nyman Veronika Rezov Veronika Rezov Brendan J. Battersby Anna-Elina Lehesjoki Anna-Elina Lehesjoki |
| author_facet | Katarin Gorski Katarin Gorski Christopher B. Jackson Tuula A. Nyman Veronika Rezov Veronika Rezov Brendan J. Battersby Anna-Elina Lehesjoki Anna-Elina Lehesjoki |
| author_sort | Katarin Gorski |
| collection | DOAJ |
| description | The involvement of mitochondrial dysfunction in cystatin B (CSTB) deficiency has been suggested, but its role in the onset of neurodegeneration, myoclonus, and ataxia in the CSTB-deficient mouse model (Cstb−/−) is yet unknown. CSTB is an inhibitor of lysosomal and nuclear cysteine cathepsins. In humans, partial loss-of-function mutations cause the progressive myoclonus epilepsy neurodegenerative disorder, EPM1. Here we applied proteome analysis and respirometry on cerebellar synaptosomes from early symptomatic (Cstb−/−) mice to identify the molecular mechanisms involved in the onset of CSTB-deficiency associated neural pathogenesis. Proteome analysis showed that CSTB deficiency is associated with differential expression of mitochondrial and synaptic proteins, and respirometry revealed a progressive impairment in mitochondrial function coinciding with the onset of myoclonus and neurodegeneration in (Cstb−/−) mice. This mitochondrial dysfunction was not associated with alterations in mitochondrial DNA copy number or membrane ultrastructure. Collectively, our results show that CSTB deficiency generates a defect in synaptic mitochondrial bioenergetics that coincides with the onset and progression of the clinical phenotypes, and thus is likely a contributor to the pathogenesis of EPM1. |
| first_indexed | 2024-04-09T13:13:16Z |
| format | Article |
| id | doaj.art-42d41ce53b244a058994c702cd443e36 |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-04-09T13:13:16Z |
| publishDate | 2023-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-42d41ce53b244a058994c702cd443e362023-05-12T05:27:22ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992023-05-011610.3389/fnmol.2023.11758511175851Progressive mitochondrial dysfunction in cerebellar synaptosomes of cystatin B-deficient miceKatarin Gorski0Katarin Gorski1Christopher B. Jackson2Tuula A. Nyman3Veronika Rezov4Veronika Rezov5Brendan J. Battersby6Anna-Elina Lehesjoki7Anna-Elina Lehesjoki8Folkhälsan Research Center, Helsinki, FinlandMedicum, Faculty of Medicine, University of Helsinki, Helsinki, FinlandDepartment of Biochemistry and Developmental Biology, Medicum, Faculty of Medicine, University of Helsinki, Helsinki, FinlandDepartment of Immunology, Oslo University Hospital, University of Oslo, Oslo, NorwayFolkhälsan Research Center, Helsinki, FinlandMedicum, Faculty of Medicine, University of Helsinki, Helsinki, FinlandInstitute of Biotechnology, University of Helsinki, Helsinki, FinlandFolkhälsan Research Center, Helsinki, FinlandMedicum, Faculty of Medicine, University of Helsinki, Helsinki, FinlandThe involvement of mitochondrial dysfunction in cystatin B (CSTB) deficiency has been suggested, but its role in the onset of neurodegeneration, myoclonus, and ataxia in the CSTB-deficient mouse model (Cstb−/−) is yet unknown. CSTB is an inhibitor of lysosomal and nuclear cysteine cathepsins. In humans, partial loss-of-function mutations cause the progressive myoclonus epilepsy neurodegenerative disorder, EPM1. Here we applied proteome analysis and respirometry on cerebellar synaptosomes from early symptomatic (Cstb−/−) mice to identify the molecular mechanisms involved in the onset of CSTB-deficiency associated neural pathogenesis. Proteome analysis showed that CSTB deficiency is associated with differential expression of mitochondrial and synaptic proteins, and respirometry revealed a progressive impairment in mitochondrial function coinciding with the onset of myoclonus and neurodegeneration in (Cstb−/−) mice. This mitochondrial dysfunction was not associated with alterations in mitochondrial DNA copy number or membrane ultrastructure. Collectively, our results show that CSTB deficiency generates a defect in synaptic mitochondrial bioenergetics that coincides with the onset and progression of the clinical phenotypes, and thus is likely a contributor to the pathogenesis of EPM1.https://www.frontiersin.org/articles/10.3389/fnmol.2023.1175851/fullmitochondriamyoclonusneurodegenerationOXPHOSsynaptosomerespiration |
| spellingShingle | Katarin Gorski Katarin Gorski Christopher B. Jackson Tuula A. Nyman Veronika Rezov Veronika Rezov Brendan J. Battersby Anna-Elina Lehesjoki Anna-Elina Lehesjoki Progressive mitochondrial dysfunction in cerebellar synaptosomes of cystatin B-deficient mice Frontiers in Molecular Neuroscience mitochondria myoclonus neurodegeneration OXPHOS synaptosome respiration |
| title | Progressive mitochondrial dysfunction in cerebellar synaptosomes of cystatin B-deficient mice |
| title_full | Progressive mitochondrial dysfunction in cerebellar synaptosomes of cystatin B-deficient mice |
| title_fullStr | Progressive mitochondrial dysfunction in cerebellar synaptosomes of cystatin B-deficient mice |
| title_full_unstemmed | Progressive mitochondrial dysfunction in cerebellar synaptosomes of cystatin B-deficient mice |
| title_short | Progressive mitochondrial dysfunction in cerebellar synaptosomes of cystatin B-deficient mice |
| title_sort | progressive mitochondrial dysfunction in cerebellar synaptosomes of cystatin b deficient mice |
| topic | mitochondria myoclonus neurodegeneration OXPHOS synaptosome respiration |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2023.1175851/full |
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