. Decrease of protein phosphatase 2A and its association with accumulation and hyperphosphorylation of tau in Down syndrome. J Alzheimers Dis. 2008 Apr;13(3):295-302. PubMed.

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  1. The protein phosphatase 2A is the major tau phosphatase in brain. Its activity has previously been determined in Alzheimer disease, but not Down syndrome (DS) brain, although both conditions share a neurofibrillary pathology. Gong and colleagues now report in postmortem DS brain tissue that (a) tau is hyperphosphorylated at multiple sites and (b) that levels of the catalytic subunit of PP2A are reduced to nearly half of that of controls. The authors furthermore negatively correlate levels of tau to the levels of the catalytic subunit C of PP2A. This, therefore, suggests that hyperphosphorylation of tau in DS brain may be caused by downregulation of PP2A.

    PP2A is a heterotrimeric enzyme composed of the C subunit that associates with the structural subunit A and one of the many members of the regulatory B subunit family. In the present study it is reported that levels of A and B are not altered (data not shown). A and B are known to be stabilized by C, so the question is what is happening to A and B when levels of C are reduced by 50 percent? It would be worthwhile to determine whether levels of distinct members of the B subunit family are altered whereas others are not. This would cause reduced PP2A activity, and hence increased phosphorylation of some, but not other, substrates (as shown by us in PP2A C dominant-negative mutant mice). This would be also interesting to know as the regulatory subunits are expected to be a much easier drug target than the catalytic subunit itself.

    In the discussion of the paper it is stated that the mechanism by which levels of PP2A C are downregulated in DS brain is not known. A regulation at the transcriptional level is discussed. As recent studies show that the mRNA quality of postmortem tissue is remarkably high, mRNA levels of the different PP2A subunits could be easily analyzed in follow-up studies.

    Together the data suggest that PP2A is an attractive target for therapeutic intervention to treat neurodegenerative diseases including DS.

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