Deficiency of RbAp48 protein and memory loss
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Memory is commonly referred to as the ability to encode, store, retain and subsequently recall information and past experiences in the human brain. This process involves many proteins, one of which is the Histone-binding protein RbAp48 ( also know as RBBP4 or NURF55), encoded by the RBBP4 gene in humans. [1]
Function
RbAp48, also known as RBBP4 gene encodes a nuclear protein, which belongs to a highly conserved family of WD40 repeat. This gene is present in many protein complexes that are involved in Histone acetylation and deacetylation processes as well as chromatin assembly.[2] This gene also belongs to the Mi-2/NuRD complex also known as Nucleosome Remodeling Deacetylase complex which plays a role in both ATP-dependent chromatin remodeling and histone deacetylase activities.[3] This protein is also part of a co-repressor complex which is a very important component of transcriptional silencing. This gene is widely available and can be found in several cellular proteins which bind directly to the retinoblastoma protein to regulate growth and cell spread.[4] This protein also found in the transcriptional repression of E2F-responsive genes, which are a group of genes that code for a family of transcription factors [2]
Biochemistry
Experimental Process
To further distinguish age-related memory loss from Alzheimer's disease (AD), a subregion of the hippocampal formation called the dentate gyrus (DG) was further studied, since this regions is thought to be targeted by aging. Human postmortem tissue was collected from both DG and entorhinal cortex (EC). Entorhinal cortex is a neighboring subregion unaffected by aging and known to be implicated in age-related memory loss. After normalizing the expression of EC, 17 genes were manifested as age-related changes in the DG. Mice were used as the experimental subjects to test whether the decline of RbAp48 was related to age-related memory loss. The results were consistent with the human studies,where the level of RbAp48 protein was much lower in adults as compared to the young. To solidify these findings, magnetic resonance imaging (MRI) was performed which revealed that dysfunction occurred in the DG, correspondeding to the regionally selective decreases in histone accetylation [4]
Mechanism
The hippocampus is a brain region that has many interconnected subregions, where each region has its own distinct neuron population and each plays an important role in encoding memory. Many studies showed that people with Alzheimer's disease ameliorates memory by first acting on the entorhinal cortex (EC) which is the main region that provide the main input conduit from external sensors to hippocampus. Scientists initially identified memory loss associated with aging is an early manifestation of Alzheimer's; however, more evidence suggests that a distinct process affects a subregion of the hippocampus that receives inputs from the EC, the Dentate Gyrus (DG), causes memory deterioration.[5] The hippocampal formation, is made up of interconnected subregions, plays an extreme important role in retain memory. Each subregion is contain a specific population of neuron which has distinct molecular expression and physiological properties. As a result, these regions are vulnerable to various pathogenic mechanisms.[6] Although both Alzheimer's disease (AD) and the normal aging process affect the hippocampal,studies showed these two processes can be distinguished by two anatomical patterns of hippocampus dysfunctions. Postmorterm studies suggested that the entorhinal cortex (EC) and the subiculum are the hippocampal regions that are most effected by AD,[7] whereas the dentate gyrus (DG) are relatively preserved. In contrast to AD, normal aging process does not cause cell death or other pathognomonic abnormalities but rather, age-related memory loss is characterized by dysfunction neurons.[4] The results from MRI and studies suggest that the primary initial target of normal aging is the DG, whereas the EC is relatively preserved.[6]
Clinical Study on Human
Guided by the pattern that distinguishes age-related hippocampal dysfunction from AD, scientist from Columbia University Medical Center collected the DG from postmortem human brains that were free from any detectable brain pathology ranging from age 33 to 88. They also harvested the EC from each brain and generated a gene expression profile with Affymetrix microarray chips, where one microarray is designated to each individual and brain area.[8] Their hypothesis is driven by the analysis that the DG is preferentially affected by aging rather than AD. The gene expression in the DG was normalized to their expression in EC; the normalized values of DG were then analyzed to find the correlation with age of the experimental subject. Scientists found that 17 normalized profiles showed an increase and decrease according to age, with a P ≤ 0.005, the scientists confirmed that the observed changes were not the product of age-related changes relative their abundant in the EC. One of the biggest change in term of gene expression, had a value conformed to the pattern of normal age-associated hippocampal dysfunction, was the expression of gene RbAp48. To further advance their studies, scientists collected EC and DG from an additional 10 heathly human brains with age ranging from 49 to 81. After the level of RbAp48 and actin in each single tissue were measured using Western blot, they discovered that the level of RbAp48 decreased with the increase of age. The level of mRNA also decreased as the age of the subject increased in DG ; however, the level of RbAp48 is unchanged in the EC.[4]
Clinical Study on Animal
Because RbAp48 protein is key component in histone acetylation and transcriptional regulation and in Cyclic adenosine monophosphate (cAMP)-protein kinase complex response element-binding protein CREB1 path way.[9] Since histone acetylation and the cAMP-PKA-CREB1] pathway are extremely important for normal hippocamal fucntion and aging in mouse,[10] scientists further solidify their findings by investigate RbAp48 and tested whether its modulation are the cause of age-related memory loss in mice.By studied on wild-type mice, Scientists discovered that RbAp48 expressed at a much higher level in the hippocampus, particularly in the DG. This finding is consistent with what they found in human because RbAp48 protein was less abundant in the DG of aged mice, as compared to aged human, than younger mice. In addition, the age-related reduction of RbAp48 was only detected in the DG, whereas the region of EC was preserved.[4] This finding further solidifies the previous discovery that aging only effect the DG and does not cause the dysfunction of EC.
DNA Interaction
In eukaryote cells, DNA is wrapped around an octamer of histone proteins to form nucleosomes, which fold to higher-order chromatin structures. The nucleosome comprises two copies of histone H3 and histone H4, which form a heterotetramer and bind DNA in the first step of nucleosome assembly. When DNA is replicated, nucleosomes need to be disassembled in front of the fork and the histones must then be transferred to the newly duplicated strands for reassembly. Studies of the in vivo composition of histone H3 complexes as well as structural study of the ASF1-H3-H4 complex, have shown that histone H3-H4 complexes are handled as a protein dimer.[11] Proteins RbAp48 is a key player in the assembly of nucleosomes.[12] RbAp48 protein is a subunit of the chromatin-assembly factor-1 (CAF-1) complex, which assembles histones H3 and H4 onto newly replicated DNA to initiate nucleosomes assembly.[13] RbAp48 protein is also found in numerous other protein complexes in regulation of chromatin structure. Studies showed that RbAp48 interacts with H3-H4 dimers and implied that RbAp48 and its function involved in numerous process such as chromatin assembly, remodeling and modifications; therefore,in many other chromatin-related process, histones H3-H4 might be handled as dimers. More generally, it seems plausible that the presence of RbAp48 may reflex the post-translational modification of nucleosome this affect the activity of neuron and ultimately affect the encoding of memory [12]
Cellular Function
- Histone acetylation and transcriptional regulation
- It has been know for some time that histone acetylation is intimately connected with transcriptional regulation.[14]
- Chromatin function and acetylation
- A direct link between chromatin function and acetylation was established by the discovery that co-activator complexes required for transcriptional activation function as histone acetyltransferases, whereas co-repressors containing histone deacetylases confer transriptional repression. Histones are locally modified on target promoters.[14]
- Histone Deacetylase Complex
CREB complex
Protein interaction
- SIN3
- BRCA1
- CREBBP [15]
References
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{{cite journal}}: Check date values in:|date=and|year=/|date=mismatch (help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help) - ^ a b "RBBP4 retinoblastoma binding protein 4". Pubmed. 8. PMID 5928. Retrieved 13 November 2013.
{{cite journal}}: Check date values in:|date=and|year=/|date=mismatch (help); Unknown parameter|month=ignored (help) - ^ Wye, Y (2). "NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities". Pubmed. 6: 851–61. PMID 9885572. Retrieved 13 November 2013.
{{cite journal}}: Check date values in:|date=and|year=/|date=mismatch (help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help) - ^ a b c d e Pavlopoulos, Elias (28). "Molecular Mechanism for Age-Related Memory Loss: The Histone-Binding Protein RbAp48". NeuroScience. 5 (200): 200ra115. Retrieved 1 November 2013.
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- ^ a b Small, SA (7). "A pathophysiological framework of hippocampal dysfunction in ageing and disease". Retrieved 21897434.
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{{cite journal}}: Check date values in:|date=and|year=/|date=mismatch (help); Unknown parameter|month=ignored (help) - ^ a b Zhang, Wei (24). "Structural plasticity of histones H3–H4 facilitates their allosteric exchange between RbAp48 and ASF1". NATURE STRUCTURAL & MOLECULAR BIOLOGY. Retrieved 2446.
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