Human QKI blocking peptide

The genetic lesion of quakingviable (qk(v)) 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 posttranscriptional 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 qk(v) dysmyelination remains unclear. Here we report that distinct molecular mechanisms underlie the reduction of MBP and the 2 ' ,3 ' -cyclic nucleotide 3 ' -phospho-diesterase (CNP) in qkv dysmyelination. MBP transcripts bind QKI strongly and are markedly reduced in the qk(v)/qk(v) 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 qk(v) dysmyelination is unlikely to be due to translational failures, but more likely results from accelerated protein degradation.

Noise exposure causes auditory nerve (AN) degeneration and hearing deficiency, though the proximal biological consequences are not entirely understood. Most AN fibers and spiral ganglion neurons are ensheathed by myelinating glia that provide insulation and ensure rapid transmission of nerve impulses from the cochlea to the brain. Here we show that noise exposure administered to mice of either sex rapidly affects myelinating glial cells, causing molecular and cellular consequences that precede nerve degeneration. This response is characterized by demyelination, inflammation, and widespread expression changes in myelin-related genes, including the RNA splicing regulator Quaking (QKI) and numerous QKI target genes. Analysis of mice deficient in QKI revealed that QKI production in cochlear glial cells is essential for proper myelination of spiral ganglion neurons and AN fibers, and for normal hearing. Our findings implicate QKI dysregulation as a critical early component in the noise response, influencing cochlear glia function that leads to AN demyelination and, ultimately, to hearing deficiency.