Unexpected similarities between C9ORF72 and sporadic forms of ALS/FTD suggest a common disease mechanism
- Columbia University, United States
- New York Genome Center, United States
Abstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent two ends of a disease spectrum with shared clinical, genetic and pathological features. These include near ubiquitous pathological inclusions of the RNA binding protein (RBP) TDP-43, and often the presence of a GGGGCC expansion in the C9ORF72 (C9) gene. Previously we reported that the sequestration of hnRNP H altered the splicing of target transcripts in C9ALS patients (Conlon et al. 2016). Here we show that this signature also occurs in half of 50 post-mortem sporadic, non-C9 ALS/FTD brains. Furthermore, and equally surprisingly, these 'like-C9' brains also contained correspondingly high amounts of insoluble TDP-43, as well as several other disease-related RBPs, and this correlates with widespread global splicing defects. Finally, we show that the like-C9 sporadic patients, like actual C9ALS patients, were much more likely to have developed FTD. We propose that these unexpected links between C9 and sporadic ALS/FTD define a common mechanism in this disease spectrum.
Data availability
All raw RNASeq data from Target ALS samples is immediately made publicly available. Access to the data can be requested by emailing ALSData@nygenome.org.All RNASeq data from the ALS Consortium is made immediately available to all members of the Consortium and with other Consortia with whom we have a reciprocal sharing arrangement. Data have been deposited in the National Center for Biotechnology Information Gene Expression Omnibus (GEO) (accession no. GSE116622). Data will be released upon acceptance.
Article and author information
Author details
Funding
NIH Office of the Director (R35 GM 118136)
- James L Manley
NIH Office of the Director (5T32GM008798)
- Erin G Conlon
ALS Association (15-LGCA-234)
- Hemali Phatnani
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Human post-mortem brain samples were donated for research purposes by next of kin.
Copyright
© 2018, Conlon et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Unexpected similarities between C9ORF72 and sporadic forms of ALS/FTD suggest a common disease mechanism
eLife 7:e37754.
https://doi.org/10.7554/eLife.37754
Further reading
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- Biochemistry and Chemical Biology
New analyses shift the view that some forms of amyotrophic lateral sclerosis and frontotemporal dementia are due to defects in a single RNA-binding protein.
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- Biochemistry and Chemical Biology
In healthy cells, cyclin D1 is expressed during the G1 phase of the cell cycle, where it activates CDK4 and CDK6. Its dysregulation is a well-established oncogenic driver in numerous human cancers. The cancer-related function of cyclin D1 has been primarily studied by focusing on the phosphorylation of the retinoblastoma (RB) gene product. Here, using an integrative approach combining bioinformatic analyses and biochemical experiments, we show that GTSE1 (G-Two and S phases expressed protein 1), a protein positively regulating cell cycle progression, is a previously unrecognized substrate of cyclin D1–CDK4/6 in tumor cells overexpressing cyclin D1 during G1 and subsequent phases. The phosphorylation of GTSE1 mediated by cyclin D1–CDK4/6 inhibits GTSE1 degradation, leading to high levels of GTSE1 across all cell cycle phases. Functionally, the phosphorylation of GTSE1 promotes cellular proliferation and is associated with poor prognosis within a pan-cancer cohort. Our findings provide insights into cyclin D1’s role in cell cycle control and oncogenesis beyond RB phosphorylation.
