Knocking out C9ORF72 Exacerbates Axonal Trafficking Defects Associated with Hexanucleotide Repeat Expansion and Reduces Levels of Heat Shock Proteins

被引：46

作者：

Abo-Rady, Masin ^{[1
]}

Kalmbach, Norman ^{[2
]}

Pal, Arun ^{[3
]}

Schludi, Carina ^{[4
,5
]}

Janosch, Antje ^{[6
]}

Richter, Tanja ^{[7
]}

Freitag, Petra ^{[8
]}

Bickle, Marc ^{[6
]}

Kahlert, Anne-Karin ^{[8
]}

Petri, Susanne ^{[2
]}

Stefanov, Stefan ^{[1
]}

Glass, Hannes ^{[3
,9
,10
]}

Staege, Selma ^{[2
]}

Just, Walter ^{[7
]}

Bhatnagar, Rajat ^{[11
]}

Edbauer, Dieter ^{[4
,5
]}

Hermann, Andreas ^{[1
,3
,9
,10
,12
]}

Wegner, Florian ^{[2
]}

Sterneckert, Jared L. ^{[1
]}

机构：

[1] Tech Univ Dresden, Ctr Regenerat Therapies TU Dresden CRTD, D-01307 Dresden, Germany

[2] Hannover Med Sch, Dept Neurol, D-30625 Hannover, Germany

[3] Tech Univ Dresden, Dept Neurol, D-01307 Dresden, Germany

[4] German Ctr Neurodegenerat Dis DZNE, D-81377 Munich, Germany

[5] Munich Cluster Syst Neurol SyNergy, D-81377 Munich, Germany

[6] Max Planck Inst Mol Cell Biol & Genet, D-01307 Dresden, Germany

[7] Univ Ulm, Inst Human Genet, D-89081 Ulm, Germany

[8] Tech Univ Dresden, Inst Klin Genet, Med Fak Carl Gustav Carus, D-01307 Dresden, Germany

[9] Univ Rostock, Univ Med Ctr Rostock, Translat Neurodegenerat Sect Albrecht Kossel, Dept Neurol, D-18147 Rostock, Germany

[10] Univ Rostock, Univ Med Ctr Rostock, CTNR, D-18147 Rostock, Germany

[11] Verge Genom, San Francisco, CA 94080 USA

[12] German Ctr Neurodegenerat Dis DZNE Rostock Greifs, D-18147 Rostock, Germany

来源：

STEM CELL REPORTS | 2020年 / 14卷 / 03期

基金：

瑞典研究理事会; 瑞士国家科学基金会; 欧盟地平线“2020”;

关键词：

SOD1;

D O I：

10.1016/j.stemcr.2020.01.010

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

In amyotrophic lateral sclerosis (ALS) motor neurons (MNs) undergo dying-back, where the distal axon degenerates before the soma. The hexanudeotide repeat expansion (HRE) in C9ORF72 is the most common genetic cause of ALS, but the mechanism of pathogenesis is largely unknown with both gain- and loss-of-function mechanisms being proposed. To better understand C9ORF72-ALS pathogenesis, we generated isogenic induced pluripotent stem cells. MNs with HRE in C9ORF72 showed decreased axonal trafficking compared with gene corrected MNs. However, knocking out C9ORF72 did not recapitulate these changes in MNs from healthy controls, suggesting a gain-of-function mechanism. In contrast, knocking out C9ORF72 in MNs with HRE exacerbated axonal trafficking defects and increased apoptosis as well as decreased levels of HSP70 and HSP40, and inhibition of HSPs exacerbated ALS phenotypes in MNs with HRE. Therefore, we propose that the HRE in C9ORF72 induces ALS pathogenesis via a combination of gain- and loss-of-function mechanisms.

引用

页码：390 / 405

页数：16

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