Mutant beta-spectrin 4 causes auditory and motor neuropathies in quivering mice.

The autosomal recessive mouse mutation quivering (qv), which arose spontaneously in 1953, produces progressive ataxia with hind limb paralysis, deafness and tremor. Six additional spontaneous alleles, qvJ, qv2J, qv3J, qv4J, qvlnd and qvlnd2J, have been identified. Ear twitch responses (Preyer's reflex) to sound are absent in homozygous qv/qv mice, although cochlear morphology seems normal and cochlear potentials recorded at the round window are no different from those of control mice. However, responses from brainstem auditory nuclei show abnormal transmission of auditory information, indicating that, in contrast to the many known mutations causing deafness originating in the cochlea, deafness in qv is central in origin. Here we report that quivering mice carry loss-of-function mutations in the mouse beta-spectrin 4 gene (Spnb4) that cause alterations in ion channel localization in myelinated nerves; this provides a rationale for the auditory and motor neuropathies of these mice.

Hyperphosphorylation of RNA polymerase II and reduced neuronal RNA levels precede neurofibrillary tangles in Alzheimer disease.

Affected neurons of Alzheimer disease (AD) brain are distinguished by the presence of the cell cycle cdc2 kinase and mitotic phosphoepitopes. A significant body of previous data has documented a decrease in neuronal RNA levels and nucleolar volume in AD brain. Here we present evidence that integrates these seemingly distinct findings and offers an explanation for the degenerative outcome of the disease. During mitosis cdc2 phosphorylates and inhibits the major transcriptional regulator RNA polymerase II (RNAP II). We therefore investigated cdc2 phosphorylation of RNAP II in AD brain. Using the H5 and H14 monoclonal antibodies specific for the cdc2-phosphorylated sites in RNAP II, we found that the polymerase is highly phosphorylated in AD. Moreover, RNAP II in AD translocates from its normally nuclear compartment to the cytoplasm of affected neurons, where it colocalizes with cdc2. These M phase-like changes in RNAP II correlate with decreased levels of poly-A RNA in affected neurons. Significantly, they precede tau phosphorylation and neurofibrillary tangle formation. Our data support the hypothesis that inappropriate activation of the cell cycle cdc2 kinase in differentiated neurons contributes to neuronal dysfunction and degeneration in part by inhibiting RNAP II and cellular processes dependent on transcription.

Expression of Kv1.1, a Shaker-like potassium channel, is temporally regulated in embryonic neurons and glia.

Kv1.1, a Shaker-like voltage-gated potassium channel, is strongly expressed in a variety of neurons in adult rodents, in which it appears to be involved in regulating neuronal excitability. Here we show that Kv1.1 is also expressed during embryonic development in the mouse, exhibiting two transient peaks of expression around embryonic day 9.5 (E9.5) and E14.5. Using both in situ hybridization and immunocytochemistry, we have identified several cell types and tissues that express Kv1.1 RNA and protein. At E9.5, Kv1.1 RNA and protein are detected transiently in non-neuronal cells in several regions of the early CNS, including rhombomeres 3 and 5 and ventricular zones in the mesencephalon and diencephalon. At E14.5, several cell types in both the CNS and peripheral nervous system express Kv1.1, including neuronal cells (sensory ganglia and outer aspect of cerebral hemispheres) and glial cells (radial glia, satellite cells, and Schwann cell precursors). These data show that Kv1.1 is expressed transiently in a variety of neuronal and non-neuronal cells during restricted periods of embryonic development. Although the functional roles of Kv1.1 in development are not understood, the cell-specific localization and timing of expression suggest this channel may play a role in several developmental processes, including proliferation, migration, or cell-cell adhesion.