UPF1 reduces C9orf72 HRE-induced neurotoxicity in the absence of nonsense-mediated decay dysfunction

Benjamin L Zaepfel; Zhe Zhang; Kirstin Maulding; Alyssa N Coyne; Weiwei Cheng; Lindsey R Hayes; Thomas E Lloyd; Shuying Sun; Jeffrey D Rothstein

doi:10.1016/j.celrep.2021.108925

UPF1 reduces C9orf72 HRE-induced neurotoxicity in the absence of nonsense-mediated decay dysfunction

Cell Rep. 2021 Mar 30;34(13):108925. doi: 10.1016/j.celrep.2021.108925.

Authors

Benjamin L Zaepfel¹, Zhe Zhang², Kirstin Maulding³, Alyssa N Coyne⁴, Weiwei Cheng², Lindsey R Hayes⁵, Thomas E Lloyd⁶, Shuying Sun⁷, Jeffrey D Rothstein⁸

Affiliations

¹ Biochemistry, Cellular and Molecular Biology Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Molecular Biology and Genetics Department, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Cellular and Molecular Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴ 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.
⁵ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁶ 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: tlloyd4@jhmi.edu.
⁷ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: shuying.sun@jhmi.edu.
⁸ 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: jrothstein@jhmi.edu.

Abstract

Multiple cellular pathways have been suggested to be altered by the C9orf72 GGGGCC (G₄C₂) hexanucleotide repeat expansion (HRE), including aspects of RNA regulation such as nonsense-mediated decay (NMD). Here, we investigate the role that overexpression of UPF1, a protein involved in NMD, plays in mitigating neurotoxicity in multiple models of C9orf72 ALS/FTD. First, we show that NMD is not altered in our endogenous induced pluripotent stem cell (iPSC)-derived spinal neuron (iPSN) model of C9orf72 ALS (C9-ALS) or postmortem motor cortex tissue from C9-ALS patients. Unexpectedly, we find that UPF1 overexpression significantly reduces the severity of known neurodegenerative phenotypes without altering NMD function itself. UPF1 overexpression reduces poly(GP) abundance without altering the amount of repeat RNA, providing a potential mechanism by which UPF1 reduces dipeptide repeat (DPR) protein-mediated toxicity. Together, these findings indicate that UPF1 is neuroprotective in the context of C9-ALS, albeit independent of known UPF1-mediated NMD pathways.

Keywords: C9ORF72; UPF1; amyotrophic lateral sclerosis; frontotemporal dementia; induced pluripotent cells; neurons; neurotoxicity; nonsense-mediated decay.

Publication types

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

MeSH terms

Amyotrophic Lateral Sclerosis / pathology
Animals
C9orf72 Protein / metabolism*
DNA Repeat Expansion / genetics*
Disease Models, Animal
Drosophila melanogaster
HEK293 Cells
HeLa Cells
Humans
Induced Pluripotent Stem Cells
Motor Cortex / pathology
Nerve Degeneration / pathology
Neurotoxicity Syndromes / genetics*
Neurotoxicity Syndromes / pathology
Nonsense Mediated mRNA Decay / genetics*
Phenotype
Postmortem Changes
RNA / metabolism
RNA Helicases / metabolism*
Trans-Activators / metabolism*

Substances

C9orf72 Protein
Trans-Activators
RNA
RNA Helicases
UPF1 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding