THE CELLULAR NUCLEIC ACID BINDING PROTEIN REGULATES THE ALZHEIMER’S DISEASE β-SECRETASE PROTEIN BACE1

Alzheimer’s disease (AD) is the most common neurodegenerative disease affecting the elderly population and is believed to be caused by the overproduction and accumulation of the toxic amyloid beta (Aβ) peptide in the brain. Aβ is produced by two separate enzymatic cleavage events of the larger membr...

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Main Author: Holler, Christopher J
Format: Others
Published: UKnowledge 2012
Subjects:
Online Access:http://uknowledge.uky.edu/biochem_etds/12
http://uknowledge.uky.edu/cgi/viewcontent.cgi?article=1006&context=biochem_etds
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spelling ndltd-uky.edu-oai-uknowledge.uky.edu-biochem_etds-10062015-12-16T05:24:49Z THE CELLULAR NUCLEIC ACID BINDING PROTEIN REGULATES THE ALZHEIMER’S DISEASE β-SECRETASE PROTEIN BACE1 Holler, Christopher J Alzheimer’s disease (AD) is the most common neurodegenerative disease affecting the elderly population and is believed to be caused by the overproduction and accumulation of the toxic amyloid beta (Aβ) peptide in the brain. Aβ is produced by two separate enzymatic cleavage events of the larger membrane bound amyloid precursor protein, APP. The first, and rate-limiting, cleavage event is made by beta-secretase, or BACE1, and is thus an attractive therapeutic target. Our lab, as well as many others, has shown that BACE1 protein and activity are increased in late-stage sporadic AD. We have extended these findings to show that BACE1 is increased in the earliest stages of AD before the onset of significant Aβ accumulation, indicating a potential causal role in the disease. Interestingly, BACE1 mRNA levels are unchanged in AD, leading to reason that a post-transcriptional method of BACE1 regulation is altered in disease. To date, the mechanism for this aberrant post-transcriptional regulation has not been elucidated. This study has implicated the cellular nucleic acid binding protein (CNBP), a highly conserved RNA binding protein, as a positive regulator of BACE1 translation, with implications for the etiology of sporadic AD. CNBP overexpression in cultured cells or spiked into a cell-free in vitro translation system increased BACE1 protein expression without affecting BACE1 mRNA levels. Knockdown of CNBP reduced BACE1 protein and mRNA slightly. Furthermore, CNBP associated with BACE1 mRNA in cell lysates and bound directly to the BACE1 5’ UTR in vitro, which confers most of the regulatory activity. Importantly, CNBP was increased in the progression of AD and correlated with BACE1 expression. Cellular stressors (such as glucose deprivation and oxidative stress) that occur in the AD brain increase BACE1 translation and we have found that these stressors increased CNBP expression as well. Early experimental evidence suggests that CNBP may enhance BACE1 translation through a cap-independent mechanism, which is an alternative translational pathway activated by cell stress. These studies indicate that the RNA binding protein CNBP is a novel trans-acting factor important for the regulation of BACE1 protein production and may be a viable therapeutic target for AD. 2012-01-01T08:00:00Z text application/pdf http://uknowledge.uky.edu/biochem_etds/12 http://uknowledge.uky.edu/cgi/viewcontent.cgi?article=1006&context=biochem_etds Theses and Dissertations--Molecular and Cellular Biochemistry UKnowledge Alzheimer’s Disease BACE1 CNBP RNA Binding Protein Translation Molecular and Cellular Neuroscience Nervous System Diseases
collection NDLTD
format Others
sources NDLTD
topic Alzheimer’s Disease
BACE1
CNBP
RNA Binding Protein
Translation
Molecular and Cellular Neuroscience
Nervous System Diseases
spellingShingle Alzheimer’s Disease
BACE1
CNBP
RNA Binding Protein
Translation
Molecular and Cellular Neuroscience
Nervous System Diseases
Holler, Christopher J
THE CELLULAR NUCLEIC ACID BINDING PROTEIN REGULATES THE ALZHEIMER’S DISEASE β-SECRETASE PROTEIN BACE1
description Alzheimer’s disease (AD) is the most common neurodegenerative disease affecting the elderly population and is believed to be caused by the overproduction and accumulation of the toxic amyloid beta (Aβ) peptide in the brain. Aβ is produced by two separate enzymatic cleavage events of the larger membrane bound amyloid precursor protein, APP. The first, and rate-limiting, cleavage event is made by beta-secretase, or BACE1, and is thus an attractive therapeutic target. Our lab, as well as many others, has shown that BACE1 protein and activity are increased in late-stage sporadic AD. We have extended these findings to show that BACE1 is increased in the earliest stages of AD before the onset of significant Aβ accumulation, indicating a potential causal role in the disease. Interestingly, BACE1 mRNA levels are unchanged in AD, leading to reason that a post-transcriptional method of BACE1 regulation is altered in disease. To date, the mechanism for this aberrant post-transcriptional regulation has not been elucidated. This study has implicated the cellular nucleic acid binding protein (CNBP), a highly conserved RNA binding protein, as a positive regulator of BACE1 translation, with implications for the etiology of sporadic AD. CNBP overexpression in cultured cells or spiked into a cell-free in vitro translation system increased BACE1 protein expression without affecting BACE1 mRNA levels. Knockdown of CNBP reduced BACE1 protein and mRNA slightly. Furthermore, CNBP associated with BACE1 mRNA in cell lysates and bound directly to the BACE1 5’ UTR in vitro, which confers most of the regulatory activity. Importantly, CNBP was increased in the progression of AD and correlated with BACE1 expression. Cellular stressors (such as glucose deprivation and oxidative stress) that occur in the AD brain increase BACE1 translation and we have found that these stressors increased CNBP expression as well. Early experimental evidence suggests that CNBP may enhance BACE1 translation through a cap-independent mechanism, which is an alternative translational pathway activated by cell stress. These studies indicate that the RNA binding protein CNBP is a novel trans-acting factor important for the regulation of BACE1 protein production and may be a viable therapeutic target for AD.
author Holler, Christopher J
author_facet Holler, Christopher J
author_sort Holler, Christopher J
title THE CELLULAR NUCLEIC ACID BINDING PROTEIN REGULATES THE ALZHEIMER’S DISEASE β-SECRETASE PROTEIN BACE1
title_short THE CELLULAR NUCLEIC ACID BINDING PROTEIN REGULATES THE ALZHEIMER’S DISEASE β-SECRETASE PROTEIN BACE1
title_full THE CELLULAR NUCLEIC ACID BINDING PROTEIN REGULATES THE ALZHEIMER’S DISEASE β-SECRETASE PROTEIN BACE1
title_fullStr THE CELLULAR NUCLEIC ACID BINDING PROTEIN REGULATES THE ALZHEIMER’S DISEASE β-SECRETASE PROTEIN BACE1
title_full_unstemmed THE CELLULAR NUCLEIC ACID BINDING PROTEIN REGULATES THE ALZHEIMER’S DISEASE β-SECRETASE PROTEIN BACE1
title_sort cellular nucleic acid binding protein regulates the alzheimer’s disease β-secretase protein bace1
publisher UKnowledge
publishDate 2012
url http://uknowledge.uky.edu/biochem_etds/12
http://uknowledge.uky.edu/cgi/viewcontent.cgi?article=1006&context=biochem_etds
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