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Proc Natl Acad Sci U S A. 2015 Jun 23;112(25):7821-6. doi: 10.1073/pnas.1509744112. Epub 2015 Jun 8.

Amelioration of toxicity in neuronal models of amyotrophic lateral sclerosis by hUPF1.

Author information

1
Department of Neurology, University of Michigan, Ann Arbor, MI 48109; sbarmada@umich.edu gpetsko@med.cornell.edu.
2
Department of Biological Sciences, Wright State University, Dayton, OH 45435;
3
Institute of Neurologic Disease, The J. David Gladstone Institutes, San Francisco, CA 94158;
4
Department of Neurology, University of Michigan, Ann Arbor, MI 48109;
5
Department of Pathology, University of San Francisco, San Francisco, CA 94143;
6
Departments of Biochemistry and Chemistry, Brandeis University, Waltham, MA 02454;
7
Departments of Biochemistry and Chemistry, Brandeis University, Waltham, MA 02454; Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10021; sbarmada@umich.edu gpetsko@med.cornell.edu.
8
Institute of Neurologic Disease, The J. David Gladstone Institutes, San Francisco, CA 94158; Department of Neurology, University of California San Francisco Medical Center, San Francisco, CA 94143; Department of Physiology, University of California San Francisco Medical Center, San Francisco, CA 94143; Keck Program in Brain Cell Engineering, The J. David Gladstone Institutes, San Francisco, CA 94158; Taube/Koret Center for Neurodegenerative Disease Research, Hellman Foundation Alzheimer's Disease Research Program and Roddenberry Stem Cell Program, San Francisco, CA 94158.

Abstract

Over 30% of patients with amyotrophic lateral sclerosis (ALS) exhibit cognitive deficits indicative of frontotemporal dementia (FTD), suggesting a common pathogenesis for both diseases. Consistent with this hypothesis, neuronal and glial inclusions rich in TDP43, an essential RNA-binding protein, are found in the majority of those with ALS and FTD, and mutations in TDP43 and a related RNA-binding protein, FUS, cause familial ALS and FTD. TDP43 and FUS affect the splicing of thousands of transcripts, in some cases triggering nonsense-mediated mRNA decay (NMD), a highly conserved RNA degradation pathway. Here, we take advantage of a faithful primary neuronal model of ALS and FTD to investigate and characterize the role of human up-frameshift protein 1 (hUPF1), an RNA helicase and master regulator of NMD, in these disorders. We show that hUPF1 significantly protects mammalian neurons from both TDP43- and FUS-related toxicity. Expression of hUPF2, another essential component of NMD, also improves survival, whereas inhibiting NMD prevents rescue by hUPF1, suggesting that hUPF1 acts through NMD to enhance survival. These studies emphasize the importance of RNA metabolism in ALS and FTD, and identify a uniquely effective therapeutic strategy for these disorders.

KEYWORDS:

ALS; FTD; RNA binding proteins; RNA decay; neurodegeneration

PMID:
26056265
PMCID:
PMC4485101
DOI:
10.1073/pnas.1509744112
[Indexed for MEDLINE]
Free PMC Article

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