Altered expression of type 1 inositol 1,4,5-trisphosphate receptor in the Ngsk Prnp deficient mice.

Doppel protein (Dpl) is a paralog of the cellular form of prion protein (PrP(C)). Its ectopic expression in the CNS elicits significant cerebellar Purkinje cell degeneration in some lines of PrP knockout mice. However, little is known about the Dpl-mediated neurodegenerative mechanism. To understand the molecular and intracellular pathways underlying Purkinje cell degeneration, here, we investigated the regulation of calcium-release channel protein, type 1 inositol 1,4,5-trisphosphate receptor (IP(3)R1) gene in Ngsk mice. These knockout mice express high levels of Dpl and eventually develop cerebellar degeneration. We observed that the expression level of IP(3)R1 gene is reduced in the cerebella of Ngsk mice as early as 3 months of age compared with age-matched controls along with the reduction in DNA binding activity of nuclear factor of activated-T cells (NFAT) which is transcription factor of IP(3)R1. Notably, expression of PrP restored the reduced DNA binding activity of NFATc4 by Dpl. Reduced expressions of brain-derived neurotrophic factor (BDNF) and ionotropic glutamate receptor subtype 2 or B (GluR2), which are regulated by NFATc4, were also restored by PrP expression. In light of these findings, we suggest a mechanism for Dpl-mediated Purkinje cell degeneration linked to reduced gene expression of proteins related to neuronal activity. Decrease in IP(3)R1 gene expression may lead to functional deficits and ultimately death of Purkinje cells in Ngsk mice.