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ISABEL LÓPEZ DE SILANES Y MANEL ESTELLER AN. R. ACAD. NAC. FARM.

Alzheimer disease

Dysregulated synthesis and deposition of extracellular amyloid-
beta (Aß) within the central nervous system is a major characteristic
of Alzheimer disease (AD). Aß is derived from proteolytic processing
of one of multiple amyloid precursors protein (APP) isoforms.
Cleavage of the APPs generates the ß/A4 peptide, the major
component of amyloid in senile plaque. In addition to the altered Aß
levels, APP mRNA levels are elevated in brain tissue of AD patients,
and transgenic mice that overexpress APP mRNA and protein have
accelerated Aß deposition. The 3’UTR of APP mRNA contains a
contiguous 29-base C + U-rich region that appears necessary and
sufficient to control the degradation of the mRNA. Purification
studies identified two RNA-binding proteins that recognize the APP
sequence element (26). One is nucleolin and the other the
heterogeneous nuclear ribonucleoprotein C (hnRNP C), a nuclear
protein that binds U-rich RNA sequences. In cell-free mRNA decay
assays, addition of nucleolin accelerates degradation of APP mRNA,
while addition of hnRNP C stabilizes APP mRNA (27). Recently,
immunohistochemical studies have found the presence of other
AUBPs, hnRNP A2 and B1, in brains of patients with AD. In any
event, like ARE-mRNAs, the cellular decay rate of APP mRNA may
reflect a competition between destabilizing versus stabilizing
proteins. One might envision that tipping the balance to stabilization
might predispose neural tissue to APP overproduction and possibly
AD (28).

Viral infections

The ability to regulate cellular gene expression is a key aspect of
the life-cycles of a diverse array of viruses. In fact, viral infection
often results in a global shutoff of host cellular gene expression,
being host and viral mRNA stability control critical during viral
infection. For instance, simple herpes virus (HSV-1) achieves host-
shutoff through the complementary actions of two viral proteins,
ICP27 and virion host shutoff (vhs), that inhibit cellular mRNA
biogenesis and trigger global mRNA decay, respectively. Although
most cellular mRNAs are thus depleted, some instead increase in

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