G4C2 Repeat RNA Initiates a POM121-Mediated Reduction in Specific Nucleoporins in C9orf72 ALS/FTD

Alyssa N Coyne; Benjamin L Zaepfel; Lindsey Hayes; Boris Fitchman; Yuval Salzberg; En-Ching Luo; Kelly Bowen; Hannah Trost; Stefan Aigner; Frank Rigo; Gene W Yeo; Amnon Harel; Clive N Svendsen; Dhruv Sareen; Jeffrey D Rothstein

doi:10.1016/j.neuron.2020.06.027

G₄C₂ Repeat RNA Initiates a POM121-Mediated Reduction in Specific Nucleoporins in C9orf72 ALS/FTD

Neuron. 2020 Sep 23;107(6):1124-1140.e11. doi: 10.1016/j.neuron.2020.06.027. Epub 2020 Jul 15.

Authors

Alyssa N Coyne¹, Benjamin L Zaepfel², Lindsey Hayes³, Boris Fitchman⁴, Yuval Salzberg⁴, En-Ching Luo⁵, Kelly Bowen⁶, Hannah Trost⁷, Stefan Aigner⁸, Frank Rigo⁹, Gene W Yeo¹⁰, Amnon Harel⁴, Clive N Svendsen⁷, Dhruv Sareen⁷, Jeffrey D Rothstein¹¹

Affiliations

¹ Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² Biochemistry, Cellular, and Molecular Biology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴ Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel.
⁵ Bioengineering Graduate Program, University of California San Diego College of Engineering, La Jolla, CA 92037, USA.
⁶ Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁷ The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁸ Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA 92037, USA.
⁹ Ionis Pharmaceuticals, Carlsbad, CA 92010, USA.
¹⁰ Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA 92037, USA; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92037, USA.
¹¹ Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: [email protected].

Abstract

Through mechanisms that remain poorly defined, defects in nucleocytoplasmic transport and accumulations of specific nuclear-pore-complex-associated proteins have been reported in multiple neurodegenerative diseases, including C9orf72 Amyotrophic Lateral Sclerosis and Frontotemporal Dementia (ALS/FTD). Using super-resolution structured illumination microscopy, we have explored the mechanism by which nucleoporins are altered in nuclei isolated from C9orf72 induced pluripotent stem-cell-derived neurons (iPSNs). Of the 23 nucleoporins evaluated, we observed a reduction in a subset of 8, including key components of the nuclear pore complex scaffold and the transmembrane nucleoporin POM121. Reduction in POM121 appears to initiate a decrease in the expression of seven additional nucleoporins, ultimately affecting the localization of Ran GTPase and subsequent cellular toxicity in C9orf72 iPSNs. Collectively, our data suggest that the expression of expanded C9orf72 ALS/FTD repeat RNA alone affects nuclear POM121 expression in the initiation of a pathological cascade affecting nucleoporin levels within neuronal nuclei and ultimately downstream neuronal survival.

Keywords: ALS; C9orf72; FTD; POM121; neurodegeneration; nuclear pore complex.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Active Transport, Cell Nucleus
Amyotrophic Lateral Sclerosis / genetics
Amyotrophic Lateral Sclerosis / metabolism*
C9orf72 Protein / genetics*
C9orf72 Protein / metabolism
Cells, Cultured
Frontotemporal Dementia / genetics
Frontotemporal Dementia / metabolism*
HEK293 Cells
Humans
Induced Pluripotent Stem Cells / cytology
Induced Pluripotent Stem Cells / metabolism
Membrane Glycoproteins / genetics*
Membrane Glycoproteins / metabolism
Neural Stem Cells / cytology
Neural Stem Cells / metabolism
Nuclear Pore / metabolism
Nuclear Pore Complex Proteins / genetics*
Nuclear Pore Complex Proteins / metabolism

Substances

C9orf72 Protein
C9orf72 protein, human
Membrane Glycoproteins
Nuclear Pore Complex Proteins
POM121 protein, human

Supplementary concepts

Frontotemporal Dementia With Motor Neuron Disease

Abstract

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding