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
Affiliations
Benjamin L. Zaepfel
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
Zhe Zhang
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
Kirstin Maulding
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
Alyssa N. Coyne
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
Weiwei Cheng
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
Lindsey R. Hayes
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Thomas E. Lloyd
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; Corresponding author
Shuying Sun
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; Corresponding author
Jeffrey D. Rothstein
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; Corresponding author
Summary: 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.
