Alzheimer's Disease and Frontotemporal Dementias

A Review with Particular Reference to Pin1 Protein

 

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Compiled by: Julian Thorpe

Our Research into the Involvement of Pin1 in the Frontotemporal Dementias funded by 

***** See the University Press Release about our Grant *****

Compiled by: Dr. Julian R. Thorpe (last updated [portions]: December 19th., 2007)

Head of EM Division, The Sussex Centre for Advanced Microscopy, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QG, U.K.
Tel: 01273-877585 (direct line) Fax: 01273-678433
Email: J.R.Thorpe@sussex.ac.uk and home page.

Belorussian translation

Summary of Our Published Research into Pin1's Involvement in Neurodegeneration 

(Our group's articles in bold/CAPS)

The peptidyl-prolyl cis-trans isomerase protein Pin1 modulates the activity of a range of proteins involved in the cell cycle, transcription, translation, endocytosis, apoptosis and cytoskeletal stability via binding phospho-Ser/Thr-Pro motifs (see Table of Pin1 target proteins). The isomerisation of such phospho-peptidyl-prolyl bonds by Pin1, at the interface of specific kinase and phosphatase activities, can provide a novel signalling mechanism regulating dephosphorylation of specific targets in subcellular compartments. Thereby, Pin1 modulates a range of cellular activities. 

We and others had previously demonstrated neuronal Pin1 deficits in Alzheimer’s Disease (AD; Lu et al., 1999 ; THORPE ET AL., 2001) and our overall hypothesis was that such deficits might also occur in the FTD-tauopathies.

During this project, we have acquired data from a range of FTD cases which showed a redistribution of neuronal Pin1 from nuclei to the cytoplasm, with associated decreases in nuclear Pin1. Concomitant with this were significantly higher levels of recombinant Pin1 binding to (its non Pin1-bound, phosphorylated target proteins in) neurons, indicative and supportive of an endogenous Pin1 shortfall. This was true for the two non-tauopathy, as well as the six tauopathy, FTDs examined, indicating that phosphorylations other than of tau can effect this Pin1 redistribution. Immunoblotting analyses showed a strong association of Pin1 with the cytoskeletal fraction in all cases. We suggested that this Pin1 redistribution was an active and relatively early event in response to phosphorylation events during neurodegeneration (THORPE ET AL., 2004)

Such Pin1 deficits may be a susceptibility factor, as others have shown the following: Pin1 depletion causes apoptosis in HeLa cells (Lu et al., 1996); patterns of AD pathology correlate with regions of lower Pin1 expression in normal human brain (Liou et al., 2003); Pin1 knockout mice suffer neurodegeneration (Liou et al., 2003); Pin1 activity, via binding pThr668 of the amyloid protein precursor (APP), may reduce b-amyloid pathology by mediating non-amyloidogenic processing (Pastorino et al., 2006), though this is contentious (Akiyama et al., 2005); and, most importantly, Pin1 can ameliorate p-tau pathology by isomerising p-tau, facilitating its trans-specific dephosphorylation and restoring its ability to bind to and re-stabilise microtubules and thence cytoskeletal integrity (Galas et al., 2006; Hamdane et al., 2006; Lu et al., 1999). 

Our overall initial hypothesis was therefore confirmed and our supposition that the observed Pin1 deficits would be deleterious to neuronal function has seemingly been vindicated by the finding that Pin1 gene promoter  polymorphisms, which result in reduced protein expression, have been found to correlate with AD (Segat et al., 2007), though this is contentious [Lambert et al., 2006; Nowotny et al., 2007]). Also, very recent data from a Drosophila tauopathy model (Khurana et al., 2006) suggest that tau phosphorylation is upstream of cell cycle activation; this would lend more support to our hypothesis that shortfalls of endogenous Pin1 would be deleterious to neuronal function, rather than the opposing view that Pin1 might instigate neurodegeneration via cyclin D1 (and thence cell cycle) activation (Hamdane et al., 2002). Indeed, presumably in the light of recent data, this latter group previously advocating blocking Pin1 activity appear recently to be taking the opposite view (Hamdane et al., 2006)

     We have also studied the non-tauopathy, Neuronal Intermediate Filament Inclusion Disease (NIFID) in more detail and determined that the intranuclear inclusions were ultrastructurally and immunologically distinct from cytoplasmic inclusions, suggesting that abnormal protein aggregation follows separate pathways in different neuronal compartments (MOSAHEB ET AL., 2005). 

In addition to our observed Pin1 deficits in FTD cases, our data from a wide age range (2-92 yr) of normal human brain showed that even in normal neurons there are significant ageing-related nuclear Pin1 shortfalls (THORPE ET AL., 2004 and HASHEMZADEH-BONEHI ET AL., 2006) 

In ageing normal neurons we also observed a novel association of Pin1 protein with lipofuscin (HASHEMZADEH-BONEHI ET AL., 2006); the highest levels of endogenous neuronal Pin1 protein were seen to associate with granules of this age-related pigment. On the basis of the evidence of our data, we hypothesised that this association might result from oxidative stress effects upon the protein with ageing and/or neurodegeneration and its resultant clearance through the endo-/lysosomal pathway; this latter could account for our observed deficits of the protein.  Interestingly, the apparent time-of-onset of our observed neuronal Pin1 shortfalls equates to late middle age, when both lipofuscin accumulations become significant and susceptibility to late-onset neurodegenerative diseases occurs. We suggested that our data were consistent with the possibility that neuronal Pin1 deficits may be a contributory factor in neurodegeneration associated with ageing.  

Very notably, in regard to this latter point, it has recently been shown that Pin1 is oxidatively modified in MCI hippocampus, and the authors concluded that the oxidative inactivation of Pin1 could be involved in the progression from MCI to AD (Butterfield et al., 2006)

All the above data would suggest that neuronal Pin1 shortfalls may be a susceptibility factor for both neurodegeneration and ageing........... 

.........as we have suggested recently: Hashemzadeh-Bonehi L, Mosaheb S, Cairns NJ, Rulten SL, Kay JE, Phillips RG and Thorpe JR (2005) Neuronal Shortfalls and Localisation to Lipofuscin of the Cell Cycle and Tau-Regulating Protein Pin1: A Linking Susceptibility Factor for Ageing and Neurodegeneration? Second Meeting on the Molecular Mechanisms of Neurodegeneration, Aula Magna, Universita' degli Studi di Milano, Via Festa del Perdono 7, 20122 - Milano (Italy) May 7-10, 2005  

Diagrammatic Representation of Our Hypothesis on Pin1 Involvement in Ageing-Related Neurodegeneration

Figure Notes (summaries of our relevant research):

(1) THORPE ET AL., 2004: With ageing, oxidative stress, up-regulated kinase/down-regulated phosphatase activities produce phosphorylated cytoplasmic Pin1 targets to which Pin1 is re-directed, with concomitant neuronal nuclear deficits. This could lead to nuclear instability and apoptosis.

(2) HASHEMZADEH-BONEHI ET AL., 2006: Ageing leads to oxidative inactivation of Pin1, its clearance through the endo-/lysosomal pathway and accumulation in ageing-associated lipofuscin. This could progressively drain available Pin1 and be deleterious to neuronal function, especially as ageing-related neuronal nuclear Pin1 deficits onset in late middle age, when both lipofuscin accumulations become significant and susceptibility to neurodegenerative diseases occur.

(3) Hashemzadeh-Bonehi et al. (Unpublished): Our unpublished observations on Pin1 knockdown SH-SY5Y cells show axonal Pin1 deficits are not compensated and could impact on axonal plasticity and stability and disturb normal neural circuitry.

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