Biochemistry Deficiency of RbAp48 protein and memory loss

1 biochemistry

1.1 experimental process
1.2 mechanism

1.2.1 clinical study on human
1.2.2 clinical study on animal


1.3 dna interaction

biochemistry
experimental process

to further distinguish age-related memory loss alzheimer s disease (ad), subregion of hippocampal formation called dentate gyrus (dg) further studied, since thought targeted aging. human postmortem tissue collected both dg , entorhinal cortex (ec). entorhinal cortex neighboring subregion unaffected aging , known implicated in age-related memory loss. after normalizing expression of ec, 17 genes manifested due age-related changes in dg. mice used experimental subjects test whether decline of rbap48 related age-related memory loss. results consistent human studies, level of rbap48 protein lower in adults compared young. solidify these findings, magnetic resonance imaging (mri) performed revealed dysfunction occurred in dg, corresponding regionally selective decreases in histone acetylation.

mechanism

the hippocampus brain region has many interconnected subregions, each region having own distinct neuron populations playing important role in encoding memory. many studies showed alzheimer s disease ameliorates memory first acting on entorhinal cortex (ec) region providing main input conduit external sensors hippocampus. scientists identified memory loss associated aging manifestation of alzheimer s; however, more recent evidence suggests distinct process affects dentate gyrus (dg), subregion of hippocampus, , causes memory deterioration. hippocampal formation made of many interconnected subregions , plays vital role in retaining memory. each subregion contains specific population of neurons have distinct molecular expression , physiological properties. result, these regions vulnerable various pathogenic mechanisms. although both alzheimer s disease (ad) , normal aging process affect hippocampus, studies showed these 2 processes can distinguished 2 anatomical patterns of hippocampal dysfunctions. postmorterm studies suggest entorhinal cortex (ec) , subiculum hippocampal subregions effected ad, whereas dentate gyrus (dg) relatively preserved in cases. in contrast ad, normal aging process not cause cell death or other pathognomonic abnormalities result in memory loss. rather, age-related memory loss characterized dysfunctioning neurons. these results mri , other studies suggest primary initial target of normal aging dg, whereas ec relatively preserved.

clinical study on human

guided pattern distinguishes age-related hippocampal dysfunction ad, scientists columbia university medical center collected dentate gyrus (dg) postmortem human brains. these dg free detectable brain pathology. these experimental subjects dg taken ranged 33 88 years of age. scientist harvested ec each brain , generated gene expression profiles affymetrix microarray chips, each microarray customized each individual s brain area. hypothesis driven analysis dg preferentially affected aging rather ad. gene expression in dg normalized expression in ec; normalized values of dg analyzed find correlation between age of experimental subjects. scientists found 17 normalized profiles showed increase , decrease correlation age. p ≤ 0.005, scientists confirmed observed changes not product of age-related change rather product of relative abundance in ec. 1 of biggest change in terms of gene expression expression of gene rbap48, p value conformed pattern of normal age-associated hippocampal dysfunction. further advance studies, scientists collected ec , dg additional 10 healthy human brains ages ranging 49 81 years. after level of rbap48 , actin in every single tissue measured using western blot, discovered level of rbap48 decreased increasing age. level of mrna decreased age of subject increased in dg ; however, level of rbap48 remained unchanged in ec.

clinical study on animal

in mice, rbap48 protein key component in histone acetylation, transcriptional regulation , in cyclic adenosine monophosphate (camp)-protein kinase element-binding protein creb1 path way. since histone acetylation , camp-pka-creb1 pathway extremely important normal hippocampal function , aging in mice, scientists further investigate rbap48 test whether modulation cause of age-related memory losses in animals, mice. studying wild-type mice, scientists discovered rbap48 expressed @ higher level in hippocampus, particularly in dentate gyrus (dg). finding consistent found in mice tissue because rbap48 protein less abundant in dg of adult mice, compared lower expression level in adult. in addition, age-related reduction of rbap48 detected in dg, whereas region of ec preserved. finding further solidifies previous discovery aging affects dg , not cause dysfunction of ec.

dna interaction

the crystal structure of nucleosome core particle h3 , h4 coloured in blue , green respectively.dna coloured gray

in eukaryotic cells, dna wrapped around octamer of histone proteins form nucleosomes, fold higher-order chromatin structures. nucleosome comprises 2 copies of histone h3 , histone h4. these nucleosomes form heterotetramer , bind dna in first step of nucleosome assembly. when dna replicated, nucleosomes need disassembled in front of fork , histones must transferred newly duplicated strands reassembly. studies of in- vivo composition of histone h3 complexes, structural of asf1-h3-h4 complex, have shown histone h3-h4 complexes handled protein dimer.

proteins rbap48 key player in assembly of nucleosomes. rbap48 protein subunit of chromatin-assembly factor-1 (caf-1) complex, assembles histones h3 , h4 onto newly replicated dna initiate nucleosomes assembly. rbap48 protein found in numerous other protein complexes regulation of chromatin structure. studies show rbap48 interacts h3-h4 dimers , imply function of rbap48 involved in numerous process such chromatin assembly, remodeling , modifications; therefore, in many other chromatin-related processes, histones h3-h4 might handled dimer. more generally, seems plausible presence of rbap48 may reflex post-translational modifications of nucleosome. result, can affect activities of neurons , impact memory encoding ability