Genome Editing in Induced Pluripotent Stem Cells Rescues TAF1 Levels in X-Linked Dystonia-Parkinsonism

被引：32

作者：

Rakovic, Aleksandar ^{[1
]}

Domingo, Aloysius ^{[1
,8
]}

Gruetz, Karen ^{[1
]}

Kulikovskaja, Leonora ^{[1
]}

Capetian, Philipp ^{[1
]}

Cowley, Sally A. ^{[2
]}

Lenz, Insa ^{[1
]}

Brueggemann, Norbert ^{[1
]}

Rosales, Raymond ^{[3
,4
]}

Jamora, Dominic ^{[5
]}

Rolfs, Arndt ^{[6
]}

Seibler, Philip ^{[1
]}

Westenberger, Ana ^{[1
]}

Koenig, Inke ^{[7
]}

Klein, Christine ^{[1
]}

机构：

[1] Univ Lubeck, Inst Neurogenet, D-23538 Lubeck, Germany

[2] Univ Oxford, Sir William Dunn Sch Pathol, Oxford, England

[3] Univ Santo Tomas, Dept Neurol, Manila, Philippines

[4] Univ Santo Tomas, Dept Psychiat, Manila, Philippines

[5] Univ Philippines, Philippine Gen Hosp, Dept Neurosci, Coll Med, Manila, Philippines

[6] Univ Rostock, Albrecht Kossel Inst Neuroregenerat AKos, Rostock, Germany

[7] Univ Lubeck, Inst Med Biometrie & Stat, Lubeck, Germany

[8] Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA

来源：

MOVEMENT DISORDERS | 2018年 / 33卷 / 07期

关键词：

parkinsonism; dystonia; induced pluripotent stem cells; genome editing; CORTICAL-NEURONS; INHIBITION; DYSFUNCTION; EXPRESSION; DYT3; GENE;

D O I：

10.1002/mds.27441

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Background: The most likely genetic cause of X-linked dystonia-parkinsonism, a neurodegenerative movement disorder endemic to the Philippines, is a 2672-bp-long retrotransposon insertion in intron 32 of the TAF1 gene. The objectives of this study were to investigate whether (1) TAF1 expression is altered in induced pluripotent stem cells and differentiated neuronal models and (2) excision of the retrotransposon insertion restores normal TAF1 expression. Methods: Expression of TAF1 and its neuronal isoform were determined in induced pluripotent stem cells and in induced pluripotent stem cell-derived cortical neurons and spiny projection neurons using quantitative PCR. Genome editing-based excision of the retrotransposon insertion was performed on induced pluripotent stem cells from 3 X-linked dystonia-parkinsonism patients. Edited and unedited induced pluripotent stem cells from X-linked dystonia-parkinsonism patients and controls were differentiated into cortical neurons and spiny projection neurons, and TAF1 expression was compared across groups. Results:TAF1 was reduced in patient-derived induced pluripotent stem cells (P<0.05) and spiny projection neurons (P<0.01). After genome editing, we observed higher TAF1 expression in edited compared with unedited induced pluripotent stem cells (P<0.0001). In edited spiny projection neurons, TAF1 expression was also increased, but did not reach statistical significance. No expression differences were observed in cortical neurons. Conclusions: (1) TAF1 reduction in X-linked dystonia-parkinsonism is likely due to the retrotransposon insertion and is recapitulated in induced pluripotent stem cells and differentiated spiny projection neurons. (2) TAF1 reduction is a tractable molecular phenotype of X-linked dystonia-parkinsonism that can be driven by excision of the retrotransposon insertion. (3) Successful rescue of the molecular phenotype in an endogenous, genome-edited model serves as a proof of principle that may successfully be transferred to other inherited neurodegenerative diseases. (C) 2018 International Parkinson and Movement Disorder Society

引用

页码：1108 / 1118

页数：11

共 16 条

[1] Dissecting the Causal Mechanism of X-Linked Dystonia-Parkinsonism by Integrating Genome and Transcriptome Assembly [J].

Aneichyk, Tatsiana ;

Hendriks, William T. ;

Yadav, Rachita ;

Shin, David ;

Gao, Dadi ;

Vaine, Christine A. ;

Collins, Ryan L. ;

Domingo, Aloysius ;

Currall, Benjamin ;

Stortchevoi, Alexei ;

Multhaupt-Buell, Trisha ;

Penney, Ellen B. ;

Cruz, Lilian ;

Dhakal, Jyotsna ;

Brand, Harrison ;

Hanscom, Carrie ;

Antolik, Caroline ;

Dy, Marisela ;

Ragavendran, Ashok ;

Underwood, Jason ;

Cantsilieris, Stuart ;

Munson, Katherine M. ;

Eichler, Evan E. ;

Acuna, Patrick ;

Go, Criscely ;

Jamora, R. Dominic G. ;

Rosales, Raymond L. ;

Church, Deanna M. ;

Williams, Stephen R. ;

Garcia, Sarah ;

Klein, Christine ;

Mueller, Ulrich ;

Wilhelmsen, Kirk C. ;

Timmers, H. T. Marc ;

Sapir, Yechiam ;

Wainger, Brian J. ;

Henderson, Daniel ;

Ito, Naoto ;

Weisenfeld, Neil ;

Jaffe, David ;

Sharma, Nutan ;

Breakefield, Xandra O. ;

Ozelius, Laurie J. ;

Bragg, D. Cristopher ;

Talkowski, Michael E. .

CELL, 2018, 172 (05) :897-+

[2] Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling [J].

Chambers, Stuart M. ;

Fasano, Christopher A. ;

Papapetrou, Eirini P. ;

Tomishima, Mark ;

Sadelain, Michel ;

Studer, Lorenz .

NATURE BIOTECHNOLOGY, 2009, 27 (03) :275-280

[3] Evidence of TAF1 dysfunction in peripheral models of X-linked dystonia-parkinsonism [J].

Domingo, Aloysius ;

Amar, David ;

Gruetz, Karen ;

Lee, Lillian V. ;

Rosales, Raymond ;

Brueggemann, Norbert ;

Jamora, Roland Dominic ;

Cutiongco-dela Paz, Eva ;

Rolfs, Arndt ;

Dressler, Dirk ;

Walter, Uwe ;

Krainc, Dimitri ;

Lohmann, Katja ;

Shamir, Ron ;

Klein, Christine ;

Westenberger, Ana .

CELLULAR AND MOLECULAR LIFE SCIENCES, 2016, 73 (16) :3205-3215

[4] New insights into the genetics of X-linked dystonia-parkinsonism (XDP, DYT3) [J].

Domingo, Aloysius ;

Westenberger, Ana ;

Lee, Lillian V. ;

Braenne, Ingrid ;

Liu, Tian ;

Vater, Inga ;

Rosales, Raymond ;

Dominic Jamora, Roland ;

Matthew Pasco, Paul ;

Maria Cutiongco-dela Paz, Eva ;

Freimann, Karen ;

Schmidt, Thomas G. P. M. ;

Dressler, Dirk ;

Kaiser, Frank J. ;

Bertram, Lars ;

Erdmann, Jeanette ;

Lohmann, Katja ;

Klein, Christine .

EUROPEAN JOURNAL OF HUMAN GENETICS, 2015, 23 (10) :1334-1340

[5] Faithful SGCE imprinting in iPSC-derived cortical neurons: an endogenous cellular model of myoclonus-dystonia [J].

Gruetz, Karen ;

Seibler, Philip ;

Weissbach, Anne ;

Lohmann, Katja ;

Carlisle, Francesca A. ;

Blake, Derek J. ;

Westenberger, Ana ;

Klein, Christine ;

Gruenewald, Anne .

SCIENTIFIC REPORTS, 2017, 7

[6] Decreased N-TAF1 expression in X-linked dystonia-parkinsonism patient-specific neural stem cells [J].

Ito, Naoto ;

Hendriks, William T. ;

Dhakal, Jyotsna ;

Vaine, Christine A. ;

Liu, Christina ;

Shin, David ;

Shin, Kyle ;

Wakabayashi-Ito, Noriko ;

Dy, Marisela ;

Multhaupt-Buell, Trisha ;

Sharma, Nutan ;

Breakefield, Xandra O. ;

Bragg, D. Cristopher .

DISEASE MODELS & MECHANISMS, 2016, 9 (04) :451-462

[7] Genetic and Epigenetic Variations in iPSCs: Potential Causes and Implications for Application [J].

Liang, Gaoyang ;

Zhang, Yi .

CELL STEM CELL, 2013, 13 (02) :149-159

[8] Reduced neuron-specific expression of the TAF1 gene is associated with X-linked dystonia-parkinsonism [J].

Makino, Satoshi ;

Kaji, Ryuji ;

Ando, Satoshi ;

Tomizawa, Maiko ;

Yasuno, Katsuhito ;

Goto, Satoshi ;

Matsumoto, Shinnichi ;

Tabuena, Ma. Daisy ;

Maranon, Elma ;

Dantes, Marita ;

Lee, Lillian V. ;

Ogasawara, Kazumasa ;

Tooyama, Ikuo ;

Akatsu, Hiroyasu ;

Nishimura, Masataka ;

Tamiya, Gen .

AMERICAN JOURNAL OF HUMAN GENETICS, 2007, 80 (03) :393-406

[9] Specific sequence changes in multiple transcript system DYT3 are associated with X-linked dystonia parkinsonism [J].

Nolte, D ;

Niemann, S ;

Müller, U .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (18) :10347-10352

[10] Efficient introduction of specific homozygous and heterozygous mutations using CRISPR/Cas9 [J].

Paquet, Dominik ;

Kwart, Dylan ;

Chen, Antonia ;

Sproul, Andrew ;

Jacob, Samson ;

Teo, Shaun ;

Olsen, Kimberly Moore ;

Gregg, Andrew ;

Noggle, Scott ;

Tessier-Lavigne, Marc .

NATURE, 2016, 533 (7601) :125-+

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