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Cerebellar Hypoplasia in Mice Lacking Selenoprotein Biosynthesis in Neurons
Selenium exerts many, if not most, of its physiological functions as a selenocysteine moiety in proteins. Selenoproteins are involved in many biochemical processes including regulation of cellular redox state, calcium homeostasis, protein biosynthesis, and degradation. A neurodevelopmental syndrome...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer US
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3984410/ https://www.ncbi.nlm.nih.gov/pubmed/24599700 http://dx.doi.org/10.1007/s12011-014-9920-z |
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author | Wirth, Eva K. Bharathi, B. Suman Hatfield, Dolph Conrad, Marcus Brielmeier, Markus Schweizer, Ulrich |
author_facet | Wirth, Eva K. Bharathi, B. Suman Hatfield, Dolph Conrad, Marcus Brielmeier, Markus Schweizer, Ulrich |
author_sort | Wirth, Eva K. |
collection | PubMed |
description | Selenium exerts many, if not most, of its physiological functions as a selenocysteine moiety in proteins. Selenoproteins are involved in many biochemical processes including regulation of cellular redox state, calcium homeostasis, protein biosynthesis, and degradation. A neurodevelopmental syndrome called progressive cerebello-cortical atrophy (PCCA) is caused by mutations in the selenocysteine synthase gene, SEPSECS, demonstrating that selenoproteins are essential for human brain development. While we have shown that selenoproteins are required for correct hippocampal and cortical interneuron development, little is known about the functions of selenoproteins in the cerebellum. Therefore, we have abrogated neuronal selenoprotein biosynthesis by conditional deletion of the gene encoding selenocysteyl tRNA([Ser]Sec) (gene symbol Trsp). Enzymatic activity of cellular glutathione peroxidase and cytosolic thioredoxin reductase is reduced in cerebellar extracts from Trsp-mutant mice. These mice grow slowly and fail to gain postural control or to coordinate their movements. Histological analysis reveals marked cerebellar hypoplasia, associated with Purkinje cell death and decreased granule cell proliferation. Purkinje cell death occurs along parasagittal stripes as observed in other models of Purkinje cell loss. Neuron-specific inactivation of glutathione peroxidase 4 (Gpx4) used the same Cre driver phenocopies tRNA([Ser]Sec) mutants in several aspects: cerebellar hypoplasia, stripe-like Purkinje cell loss, and reduced granule cell proliferation. Parvalbumin-expressing GABAergic interneurons (stellate and/or basket cells) are virtually absent in tRNA([Ser]Sec)-mutant mice, while some remained in Gpx4-mutant mice. Our data show that selenoproteins are specifically required in postmitotic neurons of the developing cerebellum, thus providing a rational explanation for cerebellar hypoplasia as occurring in PCCA patients. |
format | Online Article Text |
id | pubmed-3984410 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Springer US |
record_format | MEDLINE/PubMed |
spelling | pubmed-39844102014-04-22 Cerebellar Hypoplasia in Mice Lacking Selenoprotein Biosynthesis in Neurons Wirth, Eva K. Bharathi, B. Suman Hatfield, Dolph Conrad, Marcus Brielmeier, Markus Schweizer, Ulrich Biol Trace Elem Res Article Selenium exerts many, if not most, of its physiological functions as a selenocysteine moiety in proteins. Selenoproteins are involved in many biochemical processes including regulation of cellular redox state, calcium homeostasis, protein biosynthesis, and degradation. A neurodevelopmental syndrome called progressive cerebello-cortical atrophy (PCCA) is caused by mutations in the selenocysteine synthase gene, SEPSECS, demonstrating that selenoproteins are essential for human brain development. While we have shown that selenoproteins are required for correct hippocampal and cortical interneuron development, little is known about the functions of selenoproteins in the cerebellum. Therefore, we have abrogated neuronal selenoprotein biosynthesis by conditional deletion of the gene encoding selenocysteyl tRNA([Ser]Sec) (gene symbol Trsp). Enzymatic activity of cellular glutathione peroxidase and cytosolic thioredoxin reductase is reduced in cerebellar extracts from Trsp-mutant mice. These mice grow slowly and fail to gain postural control or to coordinate their movements. Histological analysis reveals marked cerebellar hypoplasia, associated with Purkinje cell death and decreased granule cell proliferation. Purkinje cell death occurs along parasagittal stripes as observed in other models of Purkinje cell loss. Neuron-specific inactivation of glutathione peroxidase 4 (Gpx4) used the same Cre driver phenocopies tRNA([Ser]Sec) mutants in several aspects: cerebellar hypoplasia, stripe-like Purkinje cell loss, and reduced granule cell proliferation. Parvalbumin-expressing GABAergic interneurons (stellate and/or basket cells) are virtually absent in tRNA([Ser]Sec)-mutant mice, while some remained in Gpx4-mutant mice. Our data show that selenoproteins are specifically required in postmitotic neurons of the developing cerebellum, thus providing a rational explanation for cerebellar hypoplasia as occurring in PCCA patients. Springer US 2014-03-06 2014 /pmc/articles/PMC3984410/ /pubmed/24599700 http://dx.doi.org/10.1007/s12011-014-9920-z Text en © The Author(s) 2014 https://creativecommons.org/licenses/by/4.0/ Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited. |
spellingShingle | Article Wirth, Eva K. Bharathi, B. Suman Hatfield, Dolph Conrad, Marcus Brielmeier, Markus Schweizer, Ulrich Cerebellar Hypoplasia in Mice Lacking Selenoprotein Biosynthesis in Neurons |
title | Cerebellar Hypoplasia in Mice Lacking Selenoprotein Biosynthesis in Neurons |
title_full | Cerebellar Hypoplasia in Mice Lacking Selenoprotein Biosynthesis in Neurons |
title_fullStr | Cerebellar Hypoplasia in Mice Lacking Selenoprotein Biosynthesis in Neurons |
title_full_unstemmed | Cerebellar Hypoplasia in Mice Lacking Selenoprotein Biosynthesis in Neurons |
title_short | Cerebellar Hypoplasia in Mice Lacking Selenoprotein Biosynthesis in Neurons |
title_sort | cerebellar hypoplasia in mice lacking selenoprotein biosynthesis in neurons |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3984410/ https://www.ncbi.nlm.nih.gov/pubmed/24599700 http://dx.doi.org/10.1007/s12011-014-9920-z |
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