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.