Journal
EXPERIMENTAL NEUROLOGY
Volume 199, Issue 2, Pages 328-338Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.expneurol.2005.12.030
Keywords
Pin1; lipofuscin; brain; aging; fluorescence microscopy; immunogold labeling transmission electron microscopy
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Funding
- Wellcome Trust [GR066166AIA] Funding Source: Medline
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Pin1 protein is a peptidyl-prolyl cis-trans isomerase that modulates the activity of a range of proteins involved in cell function. We and others have demonstrated neuronal Pin1 deficits in Alzheimer's disease (AD) and have shown similar deficits in frontotemporal dementia and in aging. Pin1 may, in fact, be a susceptibility factor; others have shown that Pin1 depletion causes apoptosis in HeLa cells. Further, patterns of AD pathology correlate with regions of lower Pin1 expression in normal human brain; Pin1 knockout mice suffer neurodegeneration; and Pin1 can ameliorate p-tau pathology by isomerizing p-tau, facilitating its trans-specific dephosphorylation and restoring its ability to bind to and restabilize microtubules and thence cytoskeletal integrity. Here, we report a novel localization of high levels of Pin1 with lipofuscin in aging neurons. This association could progressively drain available Pin1 and be deleterious to neuronal function during aging. We also show that Pin1 associates with lipofuscin when lipofuscin accumulations become marked and correlate with susceptibility to neurodegenerative disease. Our data are consistent with the possibility that neuronal Pin1 deficits may be a contributory factor in neurodegeneration associated with aging. (c) 2006 Elsevier Inc. All rights reserved.
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