Analysis of functional polymorphisms in three synaptic plasticity-related genes (BDNF, COMT AND UCHL1) in Alzheimer's disease in Colombia
Introduction
Alzheimer's disease (AD) is the most frequent type of dementia in the world (Wimo et al., 2003). In recent years, it has been proposed that synaptic dysfunction may be an important etiological factor for neuropsychiatric dysfunction seen in AD (Selkoe, 2002). Although this hypothesis has been widely tested and supported, using several cellular and animal models of AD and neuropathological studies in humans, (Arendt, 2004) its implications for genetic susceptibility in patients remains to be formally explored.
Recent studies have shown that the prevalence of dementia in Colombia is near 1.3% among individuals older than 50 years (Pradilla et al., 2003) and that Colombia has a higher burden of mental disorders compared to other countries (Demyttenaere et al., 2004). This is probably due to a combination of specific genetic and environmental susceptibility factors (Uhl and Grow, 2004). The population living in Bogotá (the Capital city) is composed of an European genetic background with some historical admixture with Amerindians (Yunis et al., 2000, Yunis et al., 2005).
We have reported previously a strong association with coding and promoter polymorphisms in the Apolipoprotein E (APOE) gene in our Colombian AD sample, but not with variations in other five genes (Arboleda et al., 2001, Camelo et al., 2004, Forero et al., in press, Parra-Bonilla et al., 2003). However, polymorphisms in the APOE gene only explain a fraction of the genetic risk associated with AD, and it is possible that variants in additional genes may confer an increased risk to develop AD (Warwick et al., 2000).
It is possible that variations in genes implicated in synaptic plasticity mechanisms (Kandel, 2001) may be associated with AD risk. Therefore, functional polymorphisms in genes associated to neuronal plasticity (those that have an effect on the expression or sequence of the encoded protein) may be genetic markers for AD risk. Several functional polymorphisms in synaptic plasticity-related genes have been described, including variations in: brain-derived neurotrophic factor (BDNF), catechol-O-methyl transferase (COMT) and ubiquitin carboxyl-terminal hydroxylase (UCHL1) genes.
BDNF is a neurotrophin implicated in long-term potentiation, learning and memory processes in the adult brain and is one of the early expressed genes in response to activation of the cAMP response element binding protein (CREB) pathway (Lu and Gottschalk, 2000). BDNF gene is located in chromosome 11, has 8 exons and spans 65 kb, and encodes a secreted protein of 247 amino acids (Liu et al., 2005). A functional polymorphism in the BDNF gene (Valine66Methionine, dbSNP: rs6265) has been found. Cell models have shown that Met isoforms is associated with altered distribution of BDNF to the synapse; in addition, it has been demonstrated that human carriers of Met allele have a lower performance in several cognitive domains (Egan et al., 2003, Liu et al., 2005).
COMT is an enzyme implicated in the breakdown of catecholamines (mainly dopamine) in the synapse at cerebral cortex, and is important in learning and memory processes in the adult brain (Egan et al., 2001). COMT gene is located in chromosome 22, has 6 exons and spans 27 kb, and encodes a protein of 271 amino acids (182 aa for the soluble isoform) (Shield et al., 2004). A functional polymorphism in the COMT gene (Valine152Methionine, dbSNP: rs4680) has been found. The Met isoform has a lower enzymatic activity and that there are differences in performance functioning in specific neuropsychological tests between COMT genotypes (Blasi et al., 2005, de Frias et al., 2005, Harris et al., 2005).
UCHL1 is an enzyme implicated in the ubiquitin proteasome pathway (UPP), having deubiquitinating and ubiquityl ligase activities (Liu et al., 2002). It is highly expressed in neurons, accounts for 1–2% of neuronal protein content (Wilkinson et al., 1989) and a 2–5% fraction of this protein resides in synaptic vesicles (Liu et al., 2002). In addition, there are reports suggesting a role for UCHL1 in synaptic plasticity as an immediate-early gene essential for long-term facilitation in Aplysia (Hegde et al., 1997) and in neurotransmission, learning, memory, and synaptic plasticity in mammals (Wood et al., 2005). UCHL1 gene is located in chromosome 4p14, has 9 exons and spans 10 kb (Leroy et al., 1998), and encodes a 212 amino acids protein. The main studied polymorphism in UCHL1 is a non-synonymous polymorphism at codon 18 in exon 3 (S18Y, 54 C > A; dbSNP rs5030732), that affects both UCHL1 enzymatic activities (Liu et al., 2002). This polymorphism has been inversely associated with sporadic PD (Maraganore et al., 2004).
In the present work, we explored the possibility that common functional single nucleotide polymorphisms (SNPs) in three synaptic plasticity-related genes, BDNF, COMT and UCHL1, may be risk factors for Alzheimer's disease in the Colombian population.
Section snippets
Subjects
We determined allele and genotype frequencies of BDNF, COMT and UCHL1 polymorphisms in a sample of 102 probable AD patients and 168 sex and age matched control subjects. Patients were evaluated by an interdisciplinary group in a memory clinic in Bogotá, Colombia, following the NINCDS-ADRDA criteria for the clinical diagnosis of AD (Arboleda et al., 2001, Camelo et al., 2004, Forero et al., in press, Parra-Bonilla et al., 2003). The mean age (±S.D.) of the entire sample was 73.3 years (±8.8) for
Results
The allele and genotype frequencies for the BDNF, COMT and UCHL1 polymorphisms in the complete sample and stratified by sex and family history are shown in Table 1, Table 2, Table 3. Genotype frequencies for the three polymorphisms were in Hardy–Weinberg equilibrium in patients and controls (P > 0.05).
For the BDNF polymorphism there was no significant association for the A (Met) carrier genotypes (AA + GA versus GG) or A allele (A versus G) in the total sample (P = 0.13 and 0.15), in LOAD group (P =
Discussion
A large part of the genetic explorations of AD etiology has been based in structural hypothesis (amyloid or tauist theories) of the disease, having limited success (Bertram and Tanzi, 2004). Advances in cell and animal models of AD have allowed the consolidation of a synaptic plasticity based hypothesis of AD (Arendt, 2004, Selkoe, 2002), with implications for the discovery of additional molecular pathways involved in AD pathogenesis and for the development of new diagnostic, therapeutic and
Acknowledgements
We thank Dr. Shih-Jen Tsai (Department of Psychiatry, Veterans General Hospital-Taipei, Taiwan) by giving us details about BDNF genotyping protocol. This work was supported by grants from COLCIENCIAS (1101-04-10161-2000, 1101-04-16404) and DIB-Universidad Nacional de Colombia (822018, 209002, 807080).
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Cited by (0)
- 1
Present address: Applied Molecular Genomics Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Antwerp, Belgium.
- 2
Both authors contributed equally to this work.