Literature: A-K ; L-Z ; subject area
Compiled by: Julian Thorpe
Pin1 Involvement in Tangle Formation
 | The involvement of Pin1 in AD was first demonstrated
in regard to tangles
.
In this context, Lu et al. (1999) showed that
Pin1 becomes depleted from the nucleus within Alzheimer’s diseased (AD)
neurones when it is redirected to the large amounts of hyperphosphorylated tau
associated with the ‘neurofibrillary tangles’. Our research on Pin1
has since confirmed these results at the TEM level (
Thorpe et al., 2001
). This depletion from the nucleus may ultimately contribute to
neuronal cell death (see Pin1 and Apoptosis
). |
| Lu et al.
used in vitro methods to reveal that
Pin1 bound to the phosphorylated threonine 231 (pThr 231) of p-tau and
tissue extractions of Pin1 protein showed that it becomes sequestered within
tangles. Furthermore, this leads to a shortfall of available soluble Pin1
protein. |
| Most significantly, Lu et al.'s research showed
that Pin1 could restore the ability of phosphorylated tau to bind
microtubules
(Mt) and promote Mt assembly in vitro. A possible future therapeutic
use of Pin1 was suggested. |
| Zhou et al. (2000) have subsequently demonstrated that the cis-trans isomerase action of Pin1 upon tau (and Cdc25C) facilitates their dephosphorylation by the phosphatase PP2A (the latter being conformation-specific for the trans phosphorylated Ser/Thr-Pro isomer). Thus, the isomerising action of Pin1 on these target proteins is a novel mechanism for regulating dephosphorylation of specific motifs. |
| Liou et al. (2003) have now published data on postmortem (normal and AD) human brain and Pin1 knockout mice which suggests that Pin1 may have a central role in the protection of neurons from neurodegenerative insult (including tangle formation). Please see: |
***** Review of Nature paper by K.P. Lu and colleagues on Pin1 knockout mice *****
N.B. Please visit the
VCDN site
(Cerebral Aging and Neurodegeneration at INSERM, Lille, France) for
detail on tau protein in relation to neurodegeneration
For diagram above:
(1) Lu_PJ, Wulf_G, Zhou_XZ, Davies_P, Lu_KP (1999) The prolyl isomerase Pin1
restores the function of Alzheimer-associated phosphorylated tau protein.
NATURE 399: 784-788
(2) Zhou, XZ, Kops, O, Werner, A, Lu, PJ, Shen, MH, Stoller, G, Kullertz, G, Stark, M, Fischer, G and Lu, KP (2000) Pin1 -dependent prolyl isomerization regulates dephosphorylation of Cdc25C and tau protein. MOLECULAR CELL 6: 873-883
(3) Crenshaw DG, Yang J, Means AR, Kornbluth S (1998) The mitotic peptidyl-prolyl isomerase, Pin1 , interacts with Cdc25 and Plx1 . EMBO J 17:1315-1327
(4) Harris, PLR, Zhu, XW, Pamies, C, Rottkamp, CA, Ghanbari, HA, McShea, A, Feng, Y, Ferris, DK and Smith, MA (2000) Neuronal polo-like kinase in Alzheimer disease indicates cell cycle changes. NEUROBIOLOGY OF AGING 21: 837-841
(5) Feng Y, Hodge DR, Palmieri G, Chase DL, Longo DL, Ferris DK (1999) Association of polo-like kinase with alpha-, beta- and gamma-tubulins in a stable complex. Biochemical Journal 339: 435-442
(6) Vogelsberg-Ragaglia, V, Schuck, T, Trojanowski, JQ and Lee, V. M.-Y. (2001) PP2A mRNA Expression Is Quantitatively Decreased in Alzheimer's Disease Hippocampus. Experimental Neurology 168: 402-412
(7) Thorpe JR, Morley SJ and Rulten SL (2001) Utilising the Peptidyl-Prolyl Cis-Trans Isomerase Pin1 as a Probe of its Phosphorylated Target Proteins: Examples of Binding to Nuclear Proteins in a Human Kidney Cell Line and to Tau in Alzheimer’s Diseased Brain. J. Histochem. Cytochem. 49: 97-108
General background on Pin1 references
Pin1 in AD, Apoptosis and Mitotic Events in AD references