Induced Pluripotent Stem Cells from Patients with Huntington's Disease Show CAG-Repeat-Expansion-Associated Phenotypes

被引：374

作者：

机构：

[1] The Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, 90048, CA

[2] Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, BSB 409, 8701 Watertown Plank Rd, Milwaukee, 53226, WI

[3] Departments of Neurobiology and Behavior, Psychiatry and Human Behavior, Developmental and Cell Biology and Biological Chemistry, University of California, Irvine, 92697, CA

[4] Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, 02114, MA

[5] Division of Neurobiology and Department of Psychiatry, Baltimore, 21287, MD

[6] Institute for Cell Engineering, Baltimore, 21287, MD

[7] Department of Biological Chemistry, Baltimore, 21287, MD

[8] Department of Neurology, Baltimore, 21287, MD

[9] Departments of Neuroscience and Pharmacology, Johns Hopkins University School of Medicine, Baltimore, 21287, MD

[10] Gladstone Institute of Neurological Disease, Taube-Koret Center of Huntington’s Disease Research, San Francisco, 94160, CA

[11] Departments of Neurology and Physiology, University of California, San Francisco, 94160, CA

[12] Cellular Dynamics International, Madison, 53715, WI

[13] Morgridge Institute for Research, Madison, 53715, WI

[14] School of Biosciences, Cardiff University, Museum Avenue, Cardiff

[15] Department of Pharmacological Sciences and Center for Stem Cell Research, Università degli Studi di Milano, Milano

[16] CHDI Management/CHDI Foundation, Princeton, 08540, NJ

来源：

CELL STEM CELL | 2012年 / 11卷 / 02期

关键词：

GENE-EXPRESSION CHANGES; MUTANT HUNTINGTIN; GLUTAMATE TRANSPORT; LENGTH; NEURONS; AGE; HD; TRANSCRIPTION; AGGREGATION; METABOLISM;

D O I：

10.1016/j.stem.2012.04.027

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expanded stretch of CAG trinucleotide repeats that results in neuronal dysfunction and death. Here, The HD Consortium reports the generation and characterization of 14 induced pluripotent stem cell (iPSC) lines from HD patients and controls. Microarray profiling revealed CAG-repeat-expansion-associated gene expression patterns that distinguish patient lines from controls, and early onset versus late onset HD. Differentiated HD neural cells showed disease-associated changes in electrophysiology, metabolism, cell adhesion, and ultimately cell death for lines with both medium and longer CAG repeat expansions. The longer repeat lines were however the most vulnerable to cellular stressors and BDNF withdrawal, as assessed using a range of assays across consortium laboratories. The HD iPSC collection represents a unique and well-characterized resource to elucidate disease mechanisms in HD and provides a human stem cell platform for screening new candidate therapeutics.

引用

页码：264 / 278

页数：15

共 49 条

[1] CEP-1347 reduces mutant huntingtin-associated neurotoxicity and restores BDNF levels in R6/2 mice [J].

Apostol, Barbara L. ;

Simmons, Danielle A. ;

Zuccato, ChiaFa ;

Illes, Katalin ;

Pallos, Judit ;

Casale, Malcolm ;

Conforti, Paola ;

Ramos, Catarina ;

Roarke, Margaret ;

Kathuria, Satish ;

Cattaneo, Elena ;

Marsh, J. Lawrence ;

Thompson, Leslie Michels .

MOLECULAR AND CELLULAR NEUROSCIENCE, 2008, 39 (01) :8-20

[2] Automated microscope system for determining factors that predict neuronal fate [J].

Arrasate, M ;

Finkbeiner, S .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (10) :3840-3845

[3] Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death [J].

Arrasate, M ;

Mitra, S ;

Schweitzer, ES ;

Segal, MR ;

Finkbeiner, S .

NATURE, 2004, 431 (7010) :805-810

[4] Striatal progenitors derived from human ES cells mature into DARPP32 neurons in vitro and in quinolinic acid-lesioned rats [J].

Aubry, Laetitia ;

Bugi, Aurore ;

Lefort, Nathalie ;

Rousseau, France ;

Peschanski, Marc ;

Perrier, Anselme L. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (43) :16707-16712

[5] p53 mediates cellular dysfunction and behavioral abnormalities in Huntington's disease [J].

Bae, BI ;

Xu, H ;

Igarashi, S ;

Fujimuro, M ;

Agrawal, N ;

Taya, Y ;

Hayward, SD ;

Moran, TH ;

Montell, C ;

Ross, CA ;

Snyder, SH ;

Sawa, A .

NEURON, 2005, 47 (01) :29-41

[6] Impaired glutamate transport and glutamate-glutamine cycling: downstream effects of the Huntington mutation [J].

Behrens, P. F. ;

Franz, P. ;

Woodman, B. ;

Lindenberg, K. S. ;

Landwehrmeyer, G. B. .

BRAIN, 2002, 125 :1908-1922

[7] A role for lipoprotein lipase during synaptic remodeling in the adult mouse brain [J].

Blain, JF ;

Paradis, E ;

Gaudreault, SB ;

Champagne, D ;

Richard, D ;

Poirier, J .

NEUROBIOLOGY OF DISEASE, 2004, 15 (03) :510-519

[8] Derivation of Huntington's Disease-Affected Human Embryonic Stem Cell Lines [J].

Bradley, Cara K. ;

Scott, Heather A. ;

Chami, Omar ;

Peura, Teija T. ;

Dumevska, Biljana ;

Schmidt, Uli ;

Stojanov, Tomas .

STEM CELLS AND DEVELOPMENT, 2011, 20 (03) :495-502

[9] The first reported generation of several induced pluripotent stem cell lines from homozygous and heterozygous Huntington's disease patients demonstrates mutation related enhanced lysosomal activity [J].

Camnasio, Stefano ;

Carri, Alessia Delli ;

Lombardo, Angelo ;

Grad, Iwona ;

Mariotti, Caterina ;

Castucci, Alessia ;

Rozell, Bjorn ;

Lo Riso, Pietro ;

Castiglioni, Valentina ;

Zuccato, Chiara ;

Rochon, Christelle ;

Takashima, Yasuhiro ;

Diaferia, Giuseppe ;

Biunno, Ida ;

Gellera, Cinzia ;

Jaconi, Marisa ;

Smith, Austin ;

Hovatta, Outi ;

Naldini, Luigi ;

Di Donato, Stefano ;

Feki, Anis ;

Cattaneo, Elena .

NEUROBIOLOGY OF DISEASE, 2012, 46 (01) :41-51

[10] Induced pluripotent stem cells from a spinal muscular atrophy patient [J].

Ebert, Allison D. ;

Yu, Junying ;

Rose, Ferrill F., Jr. ;

Mattis, Virginia B. ;

Lorson, Christian L. ;

Thomson, James A. ;

Svendsen, Clive N. .

NATURE, 2009, 457 (7227) :277-U1

← 1 2 3 4 5 →