DR1
Protein Dr1 (Down-regulator of transcription 1) (Negative cofactor 2-beta) (NC2-beta) (TATA-binding protein-associated phosphoprotein)
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Cathepsin D (CTSD), human leukocyte antigen DRB1 (HLA-DRB1) and apolipoprotein E (APOE) have all been associated with cognitive ability in both demented and non-demented individuals. CTSD is a pleiotrophic protein whose functions include the processing of proteins prior to presentation by HLA. Several studies have also reported that a functional exon 2 polymorphism in the CTSD gene interacts with APOEepsilon4 resulting in an increased risk of developing Alzheimer's disease (AD). We have previously reported that the CTSD exon 2 polymorphism regulates fluid intelligence. In this study, we extend this finding to other cognitive domains and investigate interactions with APOE and HLA-DRB1. Using a cohort of 766 non-demented volunteers, we found that the CTSD exon 2 T allele was associated with a decrease in several cognitive domains that comprise processing speed [random letters (RLs) test, P = 0.012; alphabet-coding task (ACT), P = 0.001], spatial recall (SR) (P = 0.016) and an additional test of fluid intelligence (P = 0.010). We also observed that the HLA-DR1 was associated with enhanced cumulative recall ability (P = 0.006), and conversely HLA-DR5 was associated with diminished delayed verbal recall and SR abilities (P = 0.014 and P = 0.003, respectively). When analysed independently, APOEepsilon4 did not influence any cognitive domains. In contrast, CTSD T/APOEepsilon4-positive volunteers scored lower on tests of fluid intelligence (P = 0.015), processing speed (ACT, P = 0.001; RL, P = 0.013) and immediate recall (P = 0.029). Scores were lower for all these tests than when CTSD and APOE were analysed independently. This supports previous findings in AD that have also reported an epistatic interaction. In addition, we found that CTSD T/HLA-DR2-positive volunteers had reduced processing speed (ACT, P = 0.040; RL, P = 0.014) and had significantly lower cumulative and SR abilities (P = 0.003 and P = 0.001, respectively). Biological interaction between these two proteins has previously been shown where HLA-DR2 binds more readily to the myelin basic protein (MBP) compared with other DR antigens, preventing MBP cleavage by CTSD.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Apolipoprotein E4
- Apolipoproteins E
- Cathepsin D
- Cognition
- Cross-Sectional Studies
- Female
- Gene Frequency
- Genotype
- HLA-DR Antigens
- HLA-DRB1 Chains
- Humans
- Male
- Memory
- Mental Processes
- Middle Aged
- Polymorphism, Genetic
- Reference Values
- Regression Analysis
A conserved hormone response element, CNTFR-DR1 (5'-AGGTCAGAGGTCAGG-3'), has been identified in the 5th intron of the alpha component of the ciliary neurotrophic factor receptor (CNTFRalpha) gene for the human TR4 orphan receptor (TR4). Electrophoretic mobility shift assay showed a specific binding with high affinity (Kd = 0.066 nM) between TR4 and the CNTFR-DR1. A reporter gene assay using chloramphenicol acetyltransferase demonstrated that the 5th intron of CNTFRalpha has an enhancer activity which could be induced by TR4 in a dose-dependent manner. Furthermore, our in situ hybridization data showed that abundant TR4 transcripts were detected in adult brain, in regions of cortical and hippocampal neurons, as well as in many developing neural structures, including brain, spinal cord, ganglia (sympathetic and sensory), and neuronal epithelia (retinal, otic, olfactory, and gustatory). The striking similarities in the expression patterns of TR4 and CNTFRalpha in the developing and postnatal nervous systems further support the potential role of TR4 in neurogenesis. Collectively, these data suggest that the human CNTFRalpha gene could represent the first identified neural-specific gene induced by TR4.
MeSH Terms
- Adult
- Aging
- Amino Acid Sequence
- Animals
- Base Sequence
- Binding Sites
- Brain
- Cerebral Cortex
- Chloramphenicol O-Acetyltransferase
- Cloning, Molecular
- Conserved Sequence
- Cricetinae
- Embryonic and Fetal Development
- Enhancer Elements, Genetic
- Epithelium
- Ganglia, Sensory
- Ganglia, Sympathetic
- Gene Expression Regulation, Developmental
- Hippocampus
- Humans
- Introns
- Mice
- Molecular Sequence Data
- Nerve Tissue Proteins
- Nervous System
- Neurons
- Receptor, Ciliary Neurotrophic Factor
- Receptors, Nerve Growth Factor
- Receptors, Steroid
- Receptors, Thyroid Hormone
- Recombinant Fusion Proteins
- Sequence Homology, Nucleic Acid
- Spinal Cord
- Transcription, Genetic
There are a few reports that associate several loci of the human leukocyte antigen (HLA) with longevity, such as DR1 which is significantly frequent in the very old, especially in Okinawa centenarians. In contrast DR9 is decreased. This report investigates 87 healthy Okinawan centenarians and 148 healthy Okinawan controls examined since 1987 with HLA phenotyping and family history questionnaires. The mean age in centenarians was 101.6 years, and that of controls was 66.4. We inquired the age and the cause of death of the parents of the subjects. Subjects whose parent's deaths were by suicide, homicide, accident, war or due to war trauma, were excluded and only those resulting from illness or natural causes were included. The relation between age of death of parents and DR types were studied. Compared to controls, DR1 was significantly increased in the centenarians (p = 0.036, RR 4.239), and DR8 was decreased (p = 0.012, RR = 0.412). When the mean age of death of parents for each DR group and that of total was determined, the mean death age of those with DR9 was significantly lower than the mean of the total (p < 0.05). More over, when the frequency rate of the DR types were compared with the parents' death age, that of DR9 decreased as the age of death increased. It is suggested that some loci of HLA-DR relate to longevity and some genetic protection against immunorelated diseases contributes to long-lived lineage.
MeSH Terms
- Aged
- Aged, 80 and over
- Case-Control Studies
- Family Health
- Gene Frequency
- HLA-DR Antigens
- Humans
- Leukocytes
- Longevity
A60 is a 60-kDa component of the axonal cortical cytoskeleton in CNS neurones. It appears to be neurone specific and is tightly bound to brain membranes. In this study the cytoskeletal activities and developmental expression of A60 in rat cerebellum have been examined using the monoclonal antibody DR1. A60 in a partially purified soluble extract of brain membranes interacts selectively with brain but not erythrocyte spectrin. Because erythrocyte spectrin is more closely related to the dendritic form of spectrin than the axonal form, this raises the possibility that A60 localises in axons by interaction with the axonal form of spectrin only. A60 is not found in rat cerebellum before the day of birth. However, during postnatal development of the cerebellum (days 1-13) DR1 reactivity appears progressively. On postnatal day 1, a small population of cells in the mantle layer (presumptive Purkinje cells) is DR1 positive. There is no DR1 reactivity found in Purkinje cell axons during their initial phase of growth. By postnatal day 7, Purkinje cell bodies, initial dendritic segments, and the cerebellar white matter are all positive. This pattern of labelling is strengthened up until postnatal day 13. By contrast, in adult rat cerebellum, the location of A60 has changed so that it is most concentrated in axons, and dendritic staining is lost. These data indicate that A60 is a spectrin-binding component of the adult axonal membrane skeleton, the presence of which is only required in axons after the initial phase of growth.
MeSH Terms
- Aging
- Animals
- Animals, Newborn
- Antibodies, Monoclonal
- Axons
- Brain
- Cell Membrane
- Cerebellum
- Chromatography, Affinity
- Chromatography, Gel
- Cytoskeletal Proteins
- Electrophoresis, Polyacrylamide Gel
- Erythrocytes
- Immunoenzyme Techniques
- Membrane Proteins
- Mice
- Molecular Weight
- Neurons
- Rats
- Rats, Sprague-Dawley
- Sheep
- Spectrin
The frequencies of 80 HLA antigen phenotypes in 82 centenarians and 20 nonagenarians in Okinawa, Japan, were compared with those in other healthy adults in various age-brackets. Subjects aged over 90 had an extremely low frequency of HLA-DRw9 and an increased frequency of DR1. In this age-group the relative risk of corrected (for number of antigens) p value for HLA-DRw9 were 5.2 and 0.0001, respectively; those for HLA-DR1 were 13.3 and 0.0367, respectively. Since a high frequency of DRw9 and a low frequency of DR1 are associated with autoimmune or immune deficiency diseases, the genetic protection against these disorders may contribute to longevity.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Female
- HLA Antigens
- HLA-D Antigens
- HLA-DR Antigens
- Humans
- Japan
- Longevity
- Male
- Middle Aged
- Phenotype