06 Aug 2003

The prolyl isomerase Pin1 protects against tau-mediated, age-dependent neurodegeneration, according to a study in the July 31 Nature. Kun Ping Lu, at Harvard Medical School, and his colleagues combine human postmortem data in AD brains with a Pin1 knockout mouse to show that Pin1 expression is inversely correlated to neuronal vulnerability and neurofibrillary tangle degeneration, and that knocking out Pin1 induces tau pathology.

Pin1, which catalyzes conformational changes leading to dephosphorylation of phosphoproteins during mitosis and other processes, has already made its debut into the AD arena. Several years ago, Lu and colleagues showed that Pin1 is reduced in AD brains, and that the enzyme can reverse tau hyperphosphorylation; they proposed that Pin1 might be neuroprotective (Lu et al., 1999; see also ARF related news story). The presence of Pin1 in tangles is also offered as evidence to bolster the case that some of the damage of AD is due to the inappropriate reactivation of certain cell-differentiation pathways (see ARF live discussion).

The evidence for a protective role of Pin1 in AD has been mixed. An early report found that Pin1 was mainly expressed in degenerating zones of the hippocampus in patients with AD, and was not expressed in nondegenerating hippocampal areas (CA1 and CA3). In the present study, Lu and colleagues found just the opposite-higher Pin1 expression in CA3 and CA4 than in tangle-prone hippocampal areas in both normal and AD brain. This contrast held true in other brain areas as well-high neuronal Pin1 expression correlated with low tangle burden and vice versa. In their Pin-1 knockout mice, Lu and colleagues observed age-dependent neuropathy, with motor and behavioral defects, along with tau hyperphosphorylation and filament formation, and neuronal degeneration.

"To our knowledge, this the first clear demonstration that endogenous mouse tau can form tau filaments. Thus, Pin1 is the first protein whose deletion has been shown to cause age-dependent neurodegeneration and tau pathologies," write the authors.

The results, add the authors, support the notion that tau phosphorylation/dephosphorylation is a dynamic process. If Pin1 expression is low (or the enzyme is increasingly sequestered in tangles), some phospho(-ser/rhr)-pro motifs in phospho-tau will not be put in proper conformation for dephosphorylation, leading to hyperphosphorylation, and eventually tangles and neurodegeneration.—Hakon Heimer