These results with ErbB4 follow the Notch story in terms of a nuclear function for a secretase-released intracellular domain. ErbB4 is then the second example and increases the likelihood that other released intracellular domains, including that from APP, will turn out to have nuclear functions, as some preliminary data already suggest. There is an increasing number of cell surface proteins that are processed by secretases, so this would seem to be a new type of signaling pathway from the cell surface to the nucleus in which the receptor acts also as a signaling transducer. It is also novel in that there is no signal amplification provided by other proteins, as, for example, in the MAP kinase pathway.

In regard to Alzheimer disease, this result may indicate that the intracellular APP fragment will have to be taken into account as a possible contributor. It is interesting that there is a developing connection between ErbB4 and schizophrenia, a disease about which very little is known at the biochemical level.

View all comments by Graham Carpenter

The study by Liu et al. indicates that microRNAs function as powerful regulators of post-transcriptional gene regulation in the adult and aging brain. The paper neatly demonstrates that when several newly identified targets of miR-34 escape regulation, late-onset brain degeneration ensues. Using the Drosophila fly as a model system, the authors could demonstrate that flies lacking miR-34 were born with no obvious defects; however, with aging these flies developed motoric dysfunction and brain degeneration.

These interesting and timely observations build on a recent body of evidence that implicates microRNAs as important molecular components of a healthy aging process.

This paper has identified some exciting and novel targets of miR-34 regulation that may be conserved. However, the targets of individual microRNAs can number in the hundreds to thousands. Indeed, this paper has identified E74A-dependent and E74A-independent pathways to disease in the absence of miR-34.

Drosophila flies expressing a polyQ disease protein (ataxin-3 polyglutamine) exhibit...  Read more

The study by Liu et al. indicates that microRNAs function as powerful regulators of post-transcriptional gene regulation in the adult and aging brain. The paper neatly demonstrates that when several newly identified targets of miR-34 escape regulation, late-onset brain degeneration ensues. Using the Drosophila fly as a model system, the authors could demonstrate that flies lacking miR-34 were born with no obvious defects; however, with aging these flies developed motoric dysfunction and brain degeneration.

These interesting and timely observations build on a recent body of evidence that implicates microRNAs as important molecular components of a healthy aging process.

This paper has identified some exciting and novel targets of miR-34 regulation that may be conserved. However, the targets of individual microRNAs can number in the hundreds to thousands. Indeed, this paper has identified E74A-dependent and E74A-independent pathways to disease in the absence of miR-34.

Drosophila flies expressing a polyQ disease protein (ataxin-3 polyglutamine) exhibit pathogenic protein inclusions. By upregulating miR-34, Liu and coworkers could demonstrate that protein inclusion formation and neurodegeneration slowed. We have recently found that miR-34b was significantly elevated in response to mHTT-Exon-1 (encoding a polyQ protein), and its blockade altered the toxicity of mHTT-Exon-1 in neuronal cell cultures (Gaughwin et al., 2011). Similar to Liu and coworkers, our data suggested that miR-34b exerts neuroprotective mechanisms in early starges of disease, but this effect is lost with disease progression.

More generally, the study highlights the true value of microRNAs as regulators of multiple co-regulated cellular processes that need to be controlled simultaneously for optimal brain aging and homeostasis. Therefore, further exploration of the biologically conserved targets of a single microRNA in biological systems that model normal brain aging will establish a diverse array of defined biochemical pathways, each with potential for therapeutic modulation. Rigorous exploration of these pathways and their relative contribution in invertebrate model systems is a powerful method to explore this further.

View all comments by Maria Björkqvist
View all comments by Philip Gaughwin