Li, Y. et al. DAPK1 variants are associated with Alzheimer's disease and allele-specific expression. Hum. Mol. Genet. 15, 2560-2568

Celera Diagnostics, Alameda, CA 94502, USA.
Human Molecular Genetics (Impact Factor: 6.39). 09/2006; 15(17):2560-8. DOI: 10.1093/hmg/ddl178
Source: PubMed


Genetic factors play an important role in the etiology of late-onset Alzheimer's disease (LOAD). We tested gene-centric single nucleotide polymorphisms (SNPs) on chromosome 9 and identified two SNPs in the death-associated protein kinase, DAPK1, that show significant association with LOAD. SNP rs4878104 was significantly associated with LOAD in our discovery case-control sample set (WU) and replicated in each of two initial validation case-control sample sets (P<0.05, UK1, SD). The risk-allele frequency of this SNP showed a similar direction in three other case-control sample sets. A meta-analysis of the six sample sets combined, totaling 2012 cases and 2336 controls, showed an allelic P-value of 0.0016 and an odds ratio (OR) of 0.87 (95%CI: 0.79-0.95). Minor allele homozygotes had a consistently lower risk than major allele homozygotes in the discovery and initial two replication sample sets, which remained significant in the meta-analysis of all six sample sets (OR=0.7, 95%CI: 0.58-0.85), whereas the risk for heterozygous subjects was not significantly different from that of major allele homozygotes. A second SNP, rs4877365, which is in high linkage disequilibrium with rs4878104 (r2=0.64), was also significantly associated with LOAD (meta P=0.0017 in the initial three sample sets). Furthermore, DAPK1 transcripts show differential allelic gene expression, and both rs4878104 and rs4877365 were significantly associated with DAPK1 allele-specific expression (P=0.015 to <0.0001). These data suggest that genetic variation in DAPK1 modulates susceptibility to LOAD.

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    • "Beta-amyloid precursor protein (APP) and presenilin 2 played major role in early-onset familial AD [4,5]. The death-associated protein kinase 1(DAPK1) [6] and ATP-binding cassette subfamily A member 7 (ABCA7) [7] have been mainly implicated with late-onset AD. The ϵ4 allele of apolipoprotein E (APOEϵ4) was the only verified risk factor for sporadic AD [8]. "
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    ABSTRACT: Cathepsin D C224T polymorphism has been reported to associate with AD susceptibility. But the results were inconsistent. This study aimed to assess the relationship between C224T polymorphism and AD risk. The relevant studies were identified by searching PubMed, Embase, Web of Science, Google Scholar and Wan fang electronic databases updated on July 2013. The relationship between Cathepsin D C224T polymorphism and AD risk was evaluated by ORs and 95% CIs. A total of 25 case-control studies including 5,602 cases and 11,049 controls were included in the meta-analysis. There was no association between C224T polymorphism and AD risk with all the studies were pooled in the meta-analysis (CT vs. CC: OR = 1.125, 95% CI = 0.974-1.299, P = 0.109; CT + TT vs. CC: OR = 1.136, 95% CI = 0.978-1.320, P = 0.094). Furthermore, when stratified by ethnicity, age of onset and APOEepsilon4 status, significant association did not found in all subgroups. The present meta-analysis suggested that the Cathepsin D C224T polymorphism was not associated with AD susceptibility.
    BMC Neurology 01/2014; 14(1):13. DOI:10.1186/1471-2377-14-13 · 2.04 Impact Factor
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    • "This is especially exciting because DAPK1 is highly expressed in the brain (Bialik and Kimchi, 2006) and its kinase activity-deficient mice are more efficient learners and have better spatial memory to wild-type mice (Yukawa et al., 2006). Moreover, DAPK1 polymorphisms are associated with susceptibility to Alzheimer's disease (Li et al., 2006). These results suggest that aberrant DAPK1 activation might contribute to age-dependent neurodegeneration in Alzheimer's disease by inhibiting Pin1 function. "
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    ABSTRACT: Pin1 is a phospho-specific prolyl isomerase that regulates numerous key signaling molecules and whose deregulation contributes to disease notably cancer. However, since prolyl isomerases are often believed to be constitutively active, little is known whether and how Pin1 catalytic activity is regulated. Here, we identify death-associated protein kinase 1 (DAPK1), a known tumor suppressor, as a kinase responsible for phosphorylation of Pin1 on Ser71 in the catalytic active site. Such phosphorylation fully inactivates Pin1 catalytic activity and inhibits its nuclear location. Moreover, DAPK1 inhibits the ability of Pin1 to induce centrosome amplification and cell transformation. Finally, Pin1 pSer71 levels are positively correlated with DAPK1 levels and negatively with centrosome amplification in human breast cancer. Thus, phosphorylation of Pin1 Ser71 by DAPK1 inhibits its catalytic activity and cellular function, providing strong evidence for an essential role of the Pin1 enzymatic activity for its cellular function.
    Molecular cell 04/2011; 42(2):147-59. DOI:10.1016/j.molcel.2011.03.005 · 14.02 Impact Factor
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    • "Bioavailable DAPK inhibitors administered during clinically relevant therapeutic time windows attenuate synaptic dysfunction and improve longer term neurological outcomes. More recent clinical data [7] has mapped an age-onset AD susceptibility locus to the DAPK gene. Therefore, there is an increasing body of evidence that links the DAPK catalytic activity to disease progression and its attenuation via use of bioavailable small molecule inhibitors of activity. "
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    ABSTRACT: Death associated protein kinase (DAPK) is a calmodulin (CaM)-regulated protein kinase that is a therapeutic target for central nervous system (CNS) disorders. We report here the results of studies that test the hypothesis of McNamara et al. (2009) that conformational selection in DAPK's glycine-rich region is key for catalytic activity. The hypothesis was tested by site-directed mutagenesis of glutamine-23 (Q23) in the middle of this loop. The glycine-rich loop exhibits localized differences in structure among DAPK conformations that correlate with different stages of the catalytic cycle. Changing the Q23 to a Valine (V23), found at the corresponding position in another CaM regulated protein kinase, results in a reduced catalytic efficiency. High resolution X-ray crystal structures of various conformations of the Q23V mutant DAPK and their superimposition with the corresponding conformations from wild type catalytic domain reveal localized changes in the glycine-rich region. The effect of the mutation on DAPK catalytic activity and the finding of only localized changes in the DAPK structure provide experimental evidence implicating conformational selection in this domain with activity. This article is part of a Special Issue entitled: 11th European Symposium on Calcium.
    Biochimica et Biophysica Acta 11/2010; 1813(5):1068-73. DOI:10.1016/j.bbamcr.2010.11.011 · 4.66 Impact Factor
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