Cerebellar hypoplasia in mice lacking selenoprotein biosynthesis in neurons
| Autor: | Ulrich Schweizer, Markus Brielmeier, Marcus Conrad, Dolph L. Hatfield, B. Suman Bharathi, Eva K. Wirth |
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| Rok vydání: | 2014 |
| Předmět: |
Cell death
Cerebellum Endocrinology Diabetes and Metabolism Developmental Disabilities Clinical Biochemistry Purkinje cell Proliferation Mice Transgenic Biology GPX4 Nervous System Malformations Biochemistry Article Inorganic Chemistry chemistry.chemical_compound Mice Selenium medicine Protein biosynthesis Animals Selenoproteins Biochemistry medical chemistry.chemical_classification Mice Knockout Neurons integumentary system Selenocysteine Biochemistry (medical) Brain General Medicine Granule cell medicine.disease Cell biology medicine.anatomical_structure chemistry nervous system Cerebellar hypoplasia (non-human) Selenoprotein Gpx4 |
| Zdroj: | Biological Trace Element Research |
| ISSN: | 1559-0720 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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