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Wirth, E.K.* ; Bharathi, B.S.* ; Hatfield, D.L.* ; Conrad, M. ; Brielmeier, M. ; Schweizer, U.*

Cerebellar hypoplasia in mice lacking selenoprotein biosynthesis in neurons.

Biol. Trace Elem. Res. 158, 203-210 (2014)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Selenium ; Brain ; Gpx4 ; Cell Death ; Proliferation; Progressive Cerebellocerebral Atrophy; Apolipoprotein-e Receptor-2; Neurological Dysfunction; Brain Selenium; Cell-death; Mouse; Gene; Selenocysteine; Expression; Deletion
Language english
Publication Year 2014
HGF-reported in Year 2014
ISSN (print) / ISBN 0163-4984
e-ISSN 1559-0720
Journal Biological Trace Element Research
Quellenangaben Volume: 158, Issue: 2, Pages: 203-210 Article Number: , Supplement: ,
Publisher Springer
Publishing Place Totowa
Reviewing status Peer reviewed
Institute(s) Institute of Developmental Genetics (IDG)
CF Comparative Medicine (AVM)
POF-Topic(s) 30204 - Cell Programming and Repair
30202 - Environmental Health
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Research field(s) Genetics and Epidemiology
PSP Element(s) G-500500-001
G-500900-001
G-500500-004
PubMed ID 24599700
DOI 10.1007/s12011-014-9920-z
WOS ID WOS:000334500000010
Scopus ID 84899654597
Erfassungsdatum 2014-05-19
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