Cui L, Jeong H, Borovecki F, Parkhurst CN, Tanese N, Krainc D.
Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration.
Cell. 2006 Oct 6;127(1):59-69.
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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.