Distinct molecular mechanisms lead to diminished myelin basic protein and 2′,3′‐cyclic nucleotide 3′‐phosphodiesterase in qkv dysmyelination

Abstract

The genetic lesion of quakingviable (qkv) causes diminished expression of the QKI RNA‐binding protein in myelin producing cells. Consequently, several structural myelin proteins are severely reduced. Among these affected proteins, the reduction of the myelin basic protein (MBP) results from post‐transcriptional abnormalities of the MBP mRNA, presumably due to the lack of interactions with QKI. However, whether this is the common mechanism for reduced expression of other myelin proteins in qkv dysmyelination remains unclear. Here we report that distinct molecular mechanisms underlie the reduction of MBP and the 2′,3′‐cyclic nucleotide 3′‐phosphodiesterase (CNP) in qkv dysmyelination. MBP transcripts bind QKI strongly and are markedly reduced in the qkv/qkv oligodendrocytes in which QKI is almost completely lost. In contrast, CNP transcripts bind QKI weakly and are only slightly affected by the lack of QKI. None the less, CNP proteins are severely reduced in the qkv/qkv brain. Since CNP transcripts are predominantly associated with translating polyribosomes, diminished CNP expression in qkv dysmyelination is unlikely to be due to translational failures, but more likely results from accelerated protein degradation.