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
- Genetics and Genomics
RNA binding proteins (RBPs) containing intrinsically disordered regions (IDRs) are present in diverse molecular complexes where they function as dynamic regulators. Their characteristics promote liquid-liquid phase separation (LLPS) and the formation of membraneless organelles such as stress granules and nucleoli. IDR-RBPs are particularly relevant in the nervous system and their dysfunction is associated with neurodegenerative diseases and brain tumor development. Serpine1 mRNA-binding protein 1 (SERBP1) is a unique member of this group, being mostly disordered and lacking canonical RNA-binding domains. We defined SERBP1’s interactome, uncovered novel roles in splicing, cell division and ribosomal biogenesis, and showed its participation in pathological stress granules and Tau aggregates in Alzheimer’s brains. SERBP1 preferentially interacts with other G-quadruplex (G4) binders, implicated in different stages of gene expression, suggesting that G4 binding is a critical component of SERBP1 function in different settings. Similarly, we identified important associations between SERBP1 and PARP1/polyADP-ribosylation (PARylation). SERBP1 interacts with PARP1 and its associated factors and influences PARylation. Moreover, protein complexes in which SERBP1 participates contain mostly PARylated proteins and PAR binders. Based on these results, we propose a feedback regulatory model in which SERBP1 influences PARP1 function and PARylation, while PARylation modulates SERBP1 functions and participation in regulatory complexes.
