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Stem Cell Reports. 2020 Mar 10;14(3):390-405. doi: 10.1016/j.stemcr.2020.01.010. Epub 2020 Feb 20.

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

Author information

1
Technische Universität Dresden, Center for Regenerative Therapies TU Dresden (CRTD), 01307 Dresden, Germany.
2
Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.
3
Department of Neurology, Technische Universität Dresden, 01307 Dresden, Germany.
4
German Center for Neurodegenerative Diseases (DZNE) and Munich Cluster for System Neurology (SyNergy), 81377 Munich, Germany.
5
Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
6
Institute of Human Genetics, University of Ulm, 89081 Ulm, Germany.
7
Institut für Klinische Genetik, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
8
Department of Neurology, Technische Universität Dresden, 01307 Dresden, Germany; Translational Neurodegeneration Section "Albrecht-Kossel", Department of Neurology and Center for Transdisciplinary Neurosciences Rostock (CTNR), University Medical Center Rostock, University of Rostock, 18147 Rostock, Germany.
9
Verge Genomics, San Francisco, CA 94080, USA.
10
Technische Universität Dresden, Center for Regenerative Therapies TU Dresden (CRTD), 01307 Dresden, Germany; Department of Neurology, Technische Universität Dresden, 01307 Dresden, Germany; Translational Neurodegeneration Section "Albrecht-Kossel", Department of Neurology and Center for Transdisciplinary Neurosciences Rostock (CTNR), University Medical Center Rostock, University of Rostock, 18147 Rostock, Germany; German Center for Neurodegenerative Diseases (DZNE) Rostock/Greifswald, 18147 Rostock, Germany.
11
Department of Neurology, Hannover Medical School, 30625 Hannover, Germany. Electronic address: wegner.florian@mh-hannover.de.
12
Technische Universität Dresden, Center for Regenerative Therapies TU Dresden (CRTD), 01307 Dresden, Germany. Electronic address: jared.sterneckert@tu-dresden.de.

Abstract

In amyotrophic lateral sclerosis (ALS) motor neurons (MNs) undergo dying-back, where the distal axon degenerates before the soma. The hexanucleotide 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.

KEYWORDS:

C9ORF72; HSP40; HSP70; amyotrophic lateral sclerosis; axonal trafficking; disease modeling; gene editing; heat shock proteins; induced pluripotent stem cells

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