Massone et al. pinpoint a small RNA that spurs cells to manufacture a particular splice variant of a key neuronal protein, potentially promoting Alzheimer's disease (AD) or other types of neurodegeneration.

Like a movie with an alternate ending, a protein can come in more than one version. Although scientists have identified numerous proteins and RNAs that influence alternative splicing, they haven't deciphered how cells fine-tune the process to produce specific protein versions. Four years ago, researchers identified a set of 30 small, noncoding RNAs manufactured by RNA polymerase III, which they suspected help regulate gene expression.

Massone et al. determined the function of one of the RNA snippets, known as 38A, that hails from an intron in the gene that encodes the potassium channel–interacting protein (KCNIP4). KCNIP4 latches onto the potassium channel Kv4, and together they ensure that neurons fire in a characteristic slow, repeating pattern. The researchers found that 38A spurs cells to produce a splice variant of KCNIP4, Var IV, that disrupts this current, potentially leading to neurodegeneration.

KCNIP4 normally interacts with γ-secretase, the enzyme complex that helps generate β-amyloid (Aβ), a protein that accumulates in the brains of AD patients. But Var IV can't make the connection, possibly disturbing Aβ processing. Supporting that notion, the researchers found that levels of 38A were more than 10 times higher in brain cells from AD patients than in controls. 38A also hiked output of the more dangerous Aβ isoform, Aβ 1-42.

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J. Cell Biol.