Reduced RAN Expression and Disrupted Transport between Cytoplasm and Nucleus; A Key Event in Alzheimer's Disease Pathophysiology

Diego Mastroeni, Leonidas Chouliaras, Andrew Grover, Winnie S. Liang, Kevin Hauns, Joseph Rogers, Paul Coleman

Research output: Contribution to journalArticle

31 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere53349
JournalPLoS One
Volume8
Issue number1
DOIs
StatePublished - Jan 8 2013
Externally publishedYes

Fingerprint

nuclear proteins
Transcription
Alzheimer disease
Nuclear Proteins
pathophysiology
in vitro studies
Alzheimer Disease
Cytoplasm
cytoplasm
transcription (genetics)
protein synthesis
nucleocytoplasmic transport
Cell Nucleus Active Transport
RNA Polymerase II
DNA
methyltransferases
Methyltransferases
DNA-directed RNA polymerase
small interfering RNA
Small Interfering RNA

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Reduced RAN Expression and Disrupted Transport between Cytoplasm and Nucleus; A Key Event in Alzheimer's Disease Pathophysiology. / Mastroeni, Diego; Chouliaras, Leonidas; Grover, Andrew; Liang, Winnie S.; Hauns, Kevin; Rogers, Joseph; Coleman, Paul.

In: PLoS One, Vol. 8, No. 1, e53349, 08.01.2013.

Research output: Contribution to journalArticle

Mastroeni, Diego ; Chouliaras, Leonidas ; Grover, Andrew ; Liang, Winnie S. ; Hauns, Kevin ; Rogers, Joseph ; Coleman, Paul. / Reduced RAN Expression and Disrupted Transport between Cytoplasm and Nucleus; A Key Event in Alzheimer's Disease Pathophysiology. In: PLoS One. 2013 ; Vol. 8, No. 1.
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