LSD1 protects against hippocampal and cortical neurodegeneration

被引：65

作者：

Christopher, Michael A. ^{[1
,2
]}

Myrick, Dexter A. ^{[1
,2
]}

Barwick, Benjamin G. ^{[2
,3
]}

Engstrom, Amanda K. ^{[1
,2
]}

Porter-Stransky, Kirsten A. ^{[4
]}

Boss, Jeremy M. ^{[3
]}

Weinshenker, David ^{[4
]}

Levey, Allan I. ^{[5
,6
]}

Katz, David J. ^{[1
]}

机构：

[1] Emory Univ, Sch Med, Dept Cell Biol, Atlanta, GA 30322 USA

[2] Emory Univ, Grad Div Biol & Biomed Sci, Atlanta, GA 30322 USA

[3] Emory Univ, Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30322 USA

[4] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA 30322 USA

[5] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA

[6] Emory Univ, Sch Med, Alzheimers Dis Res Ctr, Atlanta, GA 30322 USA

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

关键词：

FRONTOTEMPORAL LOBAR DEGENERATION; GLOBAL DNA METHYLATION; ALZHEIMERS-DISEASE; STEM-CELLS; GENE-EXPRESSION; MOUSE MODEL; R-PACKAGE; DIFFERENTIATION; ACTIVATION; COMPLEX;

D O I：

10.1038/s41467-017-00922-9

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

To investigate the mechanisms that maintain differentiated cells, here we inducibly delete the histone demethylase LSD1/KDM1A in adult mice. Loss of LSD1 leads to paralysis, along with widespread hippocampus and cortex neurodegeneration, and learning and memory defects. We focus on the hippocampus neuronal cell death, as well as the potential link between LSD1 and human neurodegenerative disease and find that loss of LSD1 induces transcription changes in common neurodegeneration pathways, along with the re-activation of stem cell genes, in the degenerating hippocampus. These data implicate LSD1 in the prevention of neurodegeneration via the inhibition of inappropriate transcription. Surprisingly, we also find that transcriptional changes in the hippocampus are similar to Alzheimer's disease (AD) and frontotemporal dementia (FTD) cases, and LSD1 is specifically mislocalized to pathological protein aggregates in these cases. These data raise the possibility that pathological aggregation could compromise the function of LSD1 in AD and FTD.

引用

页数：13

共 53 条

[21] An Epigenetic Trap Stabilizes Singular Olfactory Receptor Expression [J].

Lyons, David B. ;

Allen, William E. ;

Goh, Tracie ;

Tsai, Lulu ;

Barnea, Gilad ;

Lomvardas, Stavros .

CELL, 2013, 154 (02) :325-336

[22] Endogenous retroviruses and neighboring genes are coordinately repressed by LSD1/KDM1A [J].

Macfarlan, Todd S. ;

Gifford, Wesley D. ;

Agarwal, Saurabh ;

Driscoll, Shawn ;

Lettieri, Karen ;

Wang, Jianxun ;

Andrews, Shane E. ;

Franco, Laura ;

Rosenfeld, Michael G. ;

Ren, Bing ;

Pfaff, Samuel L. .

GENES & DEVELOPMENT, 2011, 25 (06) :594-607

[23] NEURONAL ORIGIN OF A CEREBRAL AMYLOID - NEUROFIBRILLARY TANGLES OF ALZHEIMERS-DISEASE CONTAIN THE SAME PROTEIN AS THE AMYLOID OF PLAQUE CORES AND BLOOD-VESSELS [J].

MASTERS, CL ;

MULTHAUP, G ;

SIMMS, G ;

POTTGIESSER, J ;

MARTINS, RN ;

BEYREUTHER, K .

EMBO JOURNAL, 1985, 4 (11) :2757-2763

[24] LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription [J].

Metzger, E ;

Wissmann, M ;

Yin, N ;

Müller, JM ;

Schneider, R ;

Peters, AHFM ;

Günther, T ;

Buettner, R ;

Schüle, R .

NATURE, 2005, 437 (7057) :436-439

[25] Phosphorylation of LSD1 by PKCα Is Crucial for Circadian Rhythmicity and Phase Resetting [J].

Nam, Hye Jin ;

Boo, Kyungjin ;

Kim, Dongha ;

Han, Dong-Hee ;

Choe, Han Kyoung ;

Kim, Chang Rok ;

Sun, Woong ;

Kim, Hyun ;

Kim, Kyungjin ;

Lee, Ho ;

Metzger, Eric ;

Schuele, Roland ;

Yoo, Seung-Hee ;

Takahashi, Joseph S. ;

Cho, Sehyung ;

Son, Gi Hoon ;

Baek, Sung Hee .

MOLECULAR CELL, 2014, 53 (05) :791-805

[26] Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis [J].

Neumann, Manuela ;

Sampathu, Deepak M. ;

Kwong, Linda K. ;

Truax, Adam C. ;

Micsenyi, Matthew C. ;

Chou, Thomas T. ;

Bruce, Jennifer ;

Schuck, Theresa ;

Grossman, Murray ;

Clark, Christopher M. ;

McCluskey, Leo F. ;

Miller, Bruce L. ;

Masliah, Eliezer ;

Mackenzie, Ian R. ;

Feldman, Howard ;

Feiden, Wolfgang ;

Kretzschmar, Hans A. ;

Trojanowski, John Q. ;

Lee, Virginia M. -Y. .

SCIENCE, 2006, 314 (5796) :130-133

[27] Intraneuronal β-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations:: Potential factors in amyloid plaque formation [J].

Oakley, Holly ;

Cole, Sarah L. ;

Logan, Sreemathi ;

Maus, Erika ;

Shao, Pei ;

Craft, Jeffery ;

Guillozet-Bongaarts, Angela ;

Ohno, Masuo ;

Disterhoft, John ;

Van Eldik, Linda ;

Berry, Robert ;

Vassar, Robert .

JOURNAL OF NEUROSCIENCE, 2006, 26 (40) :10129-10140

[28] Astrocyte activation and reactive gliosis [J].

Pekny, M ;

Nilsson, M .

GLIA, 2005, 50 (04) :427-434

[29] Sporadic ALS has compartment-specific aberrant exon splicing and altered cell-matrix adhesion biology [J].

Rabin, Stuart J. ;

Kim, Jae Mun 'Hugo' ;

Baughn, Michael ;

Libby, Ryan T. ;

Kim, Young Joo ;

Fan, Yuxin ;

Libby, Randell T. ;

La Spada, Albert ;

Stone, Brad ;

Ravits, John .

HUMAN MOLECULAR GENETICS, 2010, 19 (02) :313-328

[30] Heterochromatin formation in Drosophila is initiated through active removal of H3K4 methylation by the LSD1 homolog SU(VAR)3-3 [J].

Rudolph, Thomas ;

Yonezawa, Masato ;

Lein, Sandro ;

Heidrich, Kathleen ;

Kubicek, Stefan ;

Schaefer, Christiane ;

Phalke, Sameer ;

Walther, Matthias ;

Schmidt, Andreas ;

Jenuwein, Thomas ;

Reuter, Gunter .

MOLECULAR CELL, 2007, 26 (01) :103-115

← 1 2 3 4 5 6 →