Abstract
BackgroundPeptidyl-prolyl isomerase, NIMA-interacting 1 (PIN1) plays a significant role in the brain and is implicated in numerous cellular processes related to Alzheimer's disease (AD) and other neurodegenerative conditions. There are confounding results concerning PIN1 activity in AD brains. Also PIN1 genetic variation was inconsistently associated with AD risk.MethodsWe performed analysis of coding and promoter regions of PIN1 in early- and late-onset AD and frontotemporal dementia (FTD) patients in comparison with healthy controls.ResultsAnalysis of eighteen PIN1 common polymorphisms and their haplotypes in EOAD, LOAD and FTD individuals in comparison with the control group did not reveal their contribution to disease risk.In six unrelated familial AD patients four novel PIN1 sequence variants were detected. c.58+64C>T substitution that was identified in three patients, was located in an alternative exon. In silico analysis suggested that this variant highly increases a potential affinity for a splicing factor and introduces two intronic splicing enhancers. In the peripheral leukocytes of one living patient carrying the variant, a 2.82 fold decrease in PIN1 expression was observed.ConclusionOur data does not support the role of PIN1 common polymorphisms as AD risk factor. However, we suggest that the identified rare sequence variants could be directly connected with AD pathology, influencing PIN1 splicing and/or expression.
Highlights
Peptidyl-prolyl isomerase, NIMA-interacting 1 (PIN1) plays a significant role in the brain and is implicated in numerous cellular processes related to Alzheimer's disease (AD) and other neurodegenerative conditions
SNPs rs4804459, rs2233678, rs2233679 and rs2010457 were in linkage disequilibrium in late-onset Alzheimer's disease (LOAD), early onset AD (EOAD), frontotemporal dementia (FTD) and control groups (Figure 1)
Genotype and allele frequencies of investigated polymorphisms were similar in LOAD, EOAD, FTD patients in comparison with the controls
Summary
Peptidyl-prolyl isomerase, NIMA-interacting 1 (PIN1) plays a significant role in the brain and is implicated in numerous cellular processes related to Alzheimer's disease (AD) and other neurodegenerative conditions. There are confounding results concerning PIN1 activity in AD brains. Previous studies have demonstrated that PIN1 plays a crucial role in multiple cellular processes and, likewise, it has been implicated in pathogenesis of several diseases, including cancer, inflammation to neurodegenerative diseases [2,3,4,5,6,7,8]. It was shown that PIN1-catalysed conformation change of pT668 could prevent amyloidogenic processing of APP [10]. There are confounding results considering the activity and the role of PIN1 in AD [14]. Others showed that in the cortex of the frontal lobes of MCI and AD patients PIN1 levels and activity were increased compared to healthy controls [16]
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