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.
Metrics
-
- 8,682
- views
-
- 1,218
- downloads
-
- 50
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
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
-
- 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.
-
- Biochemistry and Chemical Biology
- Microbiology and Infectious Disease
Birnaviruses are a group of double-stranded RNA (dsRNA) viruses infecting birds, fish, and insects. Early endosomes (EE) constitute the platform for viral replication. Here, we study the mechanism of birnaviral targeting of EE membranes. Using the Infectious Bursal Disease Virus (IBDV) as a model, we validate that the viral protein 3 (VP3) binds to phosphatidylinositol-3-phosphate (PI3P) present in EE membranes. We identify the domain of VP3 involved in PI3P-binding, named P2 and localized in the core of VP3, and establish the critical role of the arginine at position 200 (R200), conserved among all known birnaviruses. Mutating R200 abolishes viral replication. Moreover, we propose a two-stage modular mechanism for VP3 association with EE. Firstly, the carboxy-terminal region of VP3 adsorbs on the membrane, and then the VP3 core reinforces the membrane engagement by specifically binding PI3P through its P2 domain, additionally promoting PI3P accumulation.
