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

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2013 Jan 12

PMID 23308199

Citations 34

Authors

Diego Mastroeni

Leonidas Chouliaras

Andrew Grover

Winnie S Liang

Kevin Hauns

Joseph Rogers

Paul D Coleman

Affiliations

Soon will be listed here.

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.

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References

Robertson K, Ait-Si-Ali S, Yokochi T, Wade P, Jones P, Wolffe A . DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. Nat Genet. 2000; 25(3):338-42. DOI: 10.1038/77124. View

Barres V, Ouellet V, Lafontaine J, Tonin P, Provencher D, Mes-Masson A . An essential role for Ran GTPase in epithelial ovarian cancer cell survival. Mol Cancer. 2010; 9:272. PMC: 2964620. DOI: 10.1186/1476-4598-9-272. View

Carre C, Shiekhattar R . Human GTPases associate with RNA polymerase II to mediate its nuclear import. Mol Cell Biol. 2011; 31(19):3953-62. PMC: 3187354. DOI: 10.1128/MCB.05442-11. View

Husseman J, Hallows J, Bregman D, Leverenz J, Nochlin D, Jin L . Hyperphosphorylation of RNA polymerase II and reduced neuronal RNA levels precede neurofibrillary tangles in Alzheimer disease. J Neuropathol Exp Neurol. 2002; 60(12):1219-32. DOI: 10.1093/jnen/60.12.1219. View

Liang W, Dunckley T, Beach T, Grover A, Mastroeni D, Ramsey K . Neuronal gene expression in non-demented individuals with intermediate Alzheimer's Disease neuropathology. Neurobiol Aging. 2008; 31(4):549-66. PMC: 2844804. DOI: 10.1016/j.neurobiolaging.2008.05.013. View

Muhlhausser P, Muller E, Otto A, Kutay U . Multiple pathways contribute to nuclear import of core histones. EMBO Rep. 2001; 2(8):690-6. PMC: 1084005. DOI: 10.1093/embo-reports/kve168. View

Liang W, Dunckley T, Beach T, Grover A, Mastroeni D, Ramsey K . Altered neuronal gene expression in brain regions differentially affected by Alzheimer's disease: a reference data set. Physiol Genomics. 2008; 33(2):240-56. PMC: 2826117. DOI: 10.1152/physiolgenomics.00242.2007. View

Patel V, Chu C . Nuclear transport, oxidative stress, and neurodegeneration. Int J Clin Exp Pathol. 2011; 4(3):215-29. PMC: 3071655. View

Mastroeni D, McKee A, Grover A, Rogers J, Coleman P . Epigenetic differences in cortical neurons from a pair of monozygotic twins discordant for Alzheimer's disease. PLoS One. 2009; 4(8):e6617. PMC: 2719870. DOI: 10.1371/journal.pone.0006617. View

10.

Desplats P, Spencer B, Coffee E, Patel P, Michael S, Patrick C . Alpha-synuclein sequesters Dnmt1 from the nucleus: a novel mechanism for epigenetic alterations in Lewy body diseases. J Biol Chem. 2011; 286(11):9031-7. PMC: 3059002. DOI: 10.1074/jbc.C110.212589. View

11.

Braak H, Braak E . Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991; 82(4):239-59. DOI: 10.1007/BF00308809. View

12.

Izaurralde E, Kutay U, von Kobbe C, Mattaj I, Gorlich D . The asymmetric distribution of the constituents of the Ran system is essential for transport into and out of the nucleus. EMBO J. 1997; 16(21):6535-47. PMC: 1170258. DOI: 10.1093/emboj/16.21.6535. View

13.

Bhaskar K, Miller M, Chludzinski A, Herrup K, Zagorski M, Lamb B . The PI3K-Akt-mTOR pathway regulates Abeta oligomer induced neuronal cell cycle events. Mol Neurodegener. 2009; 4:14. PMC: 2663563. DOI: 10.1186/1750-1326-4-14. View

14.

Liang W, Dunckley T, Beach T, Grover A, Mastroeni D, Walker D . Gene expression profiles in anatomically and functionally distinct regions of the normal aged human brain. Physiol Genomics. 2006; 28(3):311-22. PMC: 2259385. DOI: 10.1152/physiolgenomics.00208.2006. View

15.

Sheffield L, Miskiewicz H, Tannenbaum L, Mirra S . Nuclear pore complex proteins in Alzheimer disease. J Neuropathol Exp Neurol. 2006; 65(1):45-54. DOI: 10.1097/01.jnen.0000195939.40410.08. View

16.

de Ruijter A, van Gennip A, Caron H, Kemp S, van Kuilenburg A . Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J. 2002; 370(Pt 3):737-49. PMC: 1223209. DOI: 10.1042/BJ20021321. View

17.

Mastroeni D, Grover A, Delvaux E, Whiteside C, Coleman P, Rogers J . Epigenetic changes in Alzheimer's disease: decrements in DNA methylation. Neurobiol Aging. 2009; 31(12):2025-37. PMC: 2962691. DOI: 10.1016/j.neurobiolaging.2008.12.005. View

18.

Miyamoto Y, Saiwaki T, Yamashita J, Yasuda Y, Kotera I, Shibata S . Cellular stresses induce the nuclear accumulation of importin alpha and cause a conventional nuclear import block. J Cell Biol. 2004; 165(5):617-23. PMC: 2172376. DOI: 10.1083/jcb.200312008. View

19.

Czeko E, Seizl M, Augsberger C, Mielke T, Cramer P . Iwr1 directs RNA polymerase II nuclear import. Mol Cell. 2011; 42(2):261-6. DOI: 10.1016/j.molcel.2011.02.033. View

20.

Tesco G, Koh Y, Kang E, Cameron A, Das S, Sena-Esteves M . Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity. Neuron. 2007; 54(5):721-37. PMC: 1973166. DOI: 10.1016/j.neuron.2007.05.012. View