Abstract
Transcription of DNA is essential for cell maintenance and survival; inappropriate localization of proteins that are involved in transcription would be catastrophic. In Alzheimer's disease brains, and in vitro studies, we have found qualitative and quantitative deficits in transport into the nucleus of DNA methyltransferase 1 (DNMT1) and RNA polymerase II (RNA pol II), accompanied by their abnormal sequestration in the cytoplasm. RAN (RAs-related Nuclear protein) knockdown, by siRNA and oligomeric Aβ42 treatment in neurons, replicate human data which indicate that transport disruption in AD may be mechanistically linked to reduced expression of RAN, a pivotal molecule in nucleocytoplasmic transport. In vitro studies also indicate a significant role for oligomeric Aβ42 in the observed phenomena. We propose a model in which reduced transcription regulators in the nucleus and their increased presence in the cytoplasm may lead to many of the cellular manifestations of Alzheimer's disease.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus / drug effects
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Aged
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Aged, 80 and over
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Alzheimer Disease / genetics*
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Alzheimer Disease / metabolism
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Alzheimer Disease / pathology
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Alzheimer Disease / physiopathology*
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Amyloid beta-Peptides / pharmacology
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Autopsy
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Cell Line, Tumor
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Cell Nucleus / drug effects
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Cell Nucleus / metabolism
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Cell Nucleus / pathology
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Cerebellum / drug effects
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Cerebellum / metabolism*
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Cerebellum / pathology
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Cytoplasm / drug effects
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Cytoplasm / metabolism
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Cytoplasm / pathology
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DNA (Cytosine-5-)-Methyltransferase 1
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DNA (Cytosine-5-)-Methyltransferases / genetics
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DNA (Cytosine-5-)-Methyltransferases / metabolism
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Female
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Gene Expression Regulation / drug effects
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Humans
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Limbic System / drug effects
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Limbic System / metabolism*
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Limbic System / pathology
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Male
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Peptide Fragments / pharmacology
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RNA Polymerase II / genetics
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RNA Polymerase II / metabolism
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RNA, Small Interfering / genetics
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Signal Transduction / drug effects
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Transcription, Genetic / drug effects
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ran GTP-Binding Protein / antagonists & inhibitors
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ran GTP-Binding Protein / genetics*
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ran GTP-Binding Protein / metabolism
Substances
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Amyloid beta-Peptides
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Peptide Fragments
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RAN protein, human
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RNA, Small Interfering
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amyloid beta-protein (1-42)
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DNA (Cytosine-5-)-Methyltransferase 1
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DNA (Cytosine-5-)-Methyltransferases
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DNMT1 protein, human
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RNA Polymerase II
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ran GTP-Binding Protein