Monday, February 12, 2007

Meet DARPP-32   posted by Matt McIntosh @ 2/12/2007 07:14:00 PM

DARPP-32 is a regulatory protein with a lot going on that should be of interest to GNXP readers. It act as a master switch in the brain which regulates the activity of a variety of ion pumps, ion channels, neurotransmitter receptors, neuromodulators and transcription factors. (Paul Greengard won a richly deserved Nobel prize for doing the most of the heavy lifting in understanding the many important brain functions it plays a role in.)

DARPP-32 is crucial in the formation and control of the information pathways that carry signals between the striatum and prefrontal cortex. This makes it extremely interesting for several reasons, first and foremost being that it plays a central role in working memory (probably influencing g), motivation, attention, and reward-based learning. Secondly, it appears to be at the nexus of the action of pretty much all classes of psychotropic drugs.

Of course something this important is going to cause a lot of havoc when it doesn't work right, and as you'd expect it's been implicated in a variety of disorders -- most recently to schizophrenia. (That list is getting mighty long.) There's long been speculations about the similarities between schizophrenia and psychomimimetics (hence the name), and DARPP-32 mediation seems to provide a concrete link between the two.

Another interesting thing is that the common allele for DARPP-32 which has been linked to schizophrenia is neither a necessary nor sufficient condition for exhibiting schizophrenic pathology. Schizophrenia has also been linked to Borna virus, which is also neither sufficient nor necessary for schizophrenia to manifest. So what's most likely going on here is that this allele has historically had some fitness advantage, probably due to a cognitive boost of some sort, but also makes the whole system it regulates more succeptible to damage by environmental insults such as pathogens that can hop the blood-brain barrier (of which Borna virus is one, but probably not the only one). It's a good illustration of just how complex medical aetiology can get, and of course as Greg Cochran & Paul Ewald will tell you there are probably a lot of other unusual conditions that follow similar causal lines.