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Alzheimer-associated C allele of the promoter polymorphism -22C>T causes a critical neuron-specific decrease of
Jessie Theuns1, Jacques Remacle, Richard Killick
1Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.
Human Molecular Genetics
|April 2, 2003
Summary
Genetic variations in the presenilin 1 (PSEN1) gene promoter increase Alzheimer's disease (AD) risk. The -22C risk allele reduces PSEN1 expression in neurons, potentially by altering regulatory factor binding.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Presenilin 1 (PSEN1) gene promoter polymorphism (-22C>T) is linked to Alzheimer's disease (AD) risk.
- CC homozygosity at this polymorphism may increase AD risk by elevating amyloid-beta (Abeta) load.
Purpose of the Study:
- To investigate the functional impact of the -22C>T polymorphism on PSEN1 transcriptional activity.
- To identify regulatory elements within the PSEN1 promoter responsible for allele-specific expression.
Main Methods:
- Deletion mapping of the PSEN1 promoter.
- Transient transfection assays to assess transcriptional activity of -22C and -22T alleles.
- Analysis of regulatory factor binding affinity.
Main Results:
- The -22C risk allele demonstrated a neuron-specific, 2-fold decrease in PSEN1 promoter activity compared to the -22T allele.
- Homozygosity for the -22C allele could lead to significantly reduced PSEN1 expression in neurons.
- Deletion mapping identified a 13 bp region (-33/-20) containing a binding site for a negative regulatory factor with higher affinity for the -22C allele.
Conclusions:
- Genetic variations in the PSEN1 promoter region can alter PSEN1 expression levels in neurons.
- These alterations in PSEN1 expression, driven by the -22C risk allele, may contribute to the increased risk of Alzheimer's disease.