Shortfalls in the Peptidyl-Prolyl Cis-Trans Isomerase Protein Pin 1 in Neurons are Associated with Frontotemporal Dementias

Thorpe, Julian R, Mosaheb, Sabrina, Hashemzadeh-Bonehi, Lida, Cairns, Nigel J, Kay, John E, Morley, Simon J and Rulten, Stuart L (2004) Shortfalls in the Peptidyl-Prolyl Cis-Trans Isomerase Protein Pin 1 in Neurons are Associated with Frontotemporal Dementias. Neurobiology of Disease, 17 (2). pp. 237-249. ISSN 0969-9961

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Abstract

The peptidyl-prolyl cis-trans isomerase (PPIase) Pin1 modulates the activity of a range of target proteins involved in the cell cycle, transcription, translation, endocytosis, and apoptosis by facilitating dephosphorylation of phosphorylated serine or threonine residue preceding a proline (p-Ser/Thr-Pro) motifs catalyzed by phosphatases specific for the trans conformations. Pin1 targets include the neuronal microtubule-associated protein tau, whose dephosphorylation restores its ability to stabilize microtubules. We, and others, have shown that tau hyperphosphorylation in the neurofibrillary tangles (NFTs) of Alzheimer disease (AD) is associated with redirection of the predominantly nuclear Pin1 to the cytoplasm and with Pin1 shortfalls throughout subcellular compartments. As nuclear Pin1 depletion causes apoptosis, shortfalls in regard to both nuclear and p-tau targets may contribute to neuronal dysfunction. We report here that similar Pin1 redistribution and shortfalls occur in frontotemporal dementias (FTDs) characterized by abnormal protein aggregates of tau and other cytoskeletal proteins. This may be a unifying, contributory factor towards neuronal death in these dementias.

Item Type: Article
Additional Information: JT directed the research, was the main and corresponding author and acquired some of the data. His postgraduate student, Sabrina Mosaheb, acquired the bulk of the data, whilst his RA, Lida Hashemzadeh-Bonehi provided key biochemical input. The article demonstrates that neuronal Pin1 protein deficits may contribute towards ageing-related neurodegeneration.
Schools and Departments: School of Life Sciences > Biochemistry
Depositing User: Julian Thorpe
Date Deposited: 06 Feb 2012 18:54
Last Modified: 30 Nov 2012 17:01
URI: http://sro.sussex.ac.uk/id/eprint/18838
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