Acknowledgments:
We thank Frédéric Allain for the His-tagged TDP-43 plasmid, Cristiana Stuani for guidance on TDP-43 purification, and Martina Hallegger for guidance on TDP-43 iCLIP.
Funding:
UK Medical Research Council [MR/M008606/1 and MR/S006508/1] (PF)
UK Motor Neurone Disease Association (PF)
Rosetrees Trust (PF,AG)
UCLH NIHR Biomedical Research Centre (PF)
4 Year Wellcome Trust Studentship (OGW)
European Union’s Horizon 2020 research and innovation programme (835300-RNPdynamics) (JU)
Cancer Research UK (FC001002) (JU)
UK Medical Research Council (FC001002) (JU)
Wellcome Trust (FC001002) (JU)
Collaborative Center for X-linked Dystonia-Parkinsonism (WCL, EMCF)
Intramural Research Program of the National Institutes of Neurological Disorders and Stroke, NIH, Bethesda, MD (MEW,SEH)
Chan Zuckerberg Initiative (MEW)
The Robert Packard Center for ALS Research (MEW)
E.B. is funded by AriSLA PathensTDP project (EB)
Wolfson Foundation (AB)
Brightfocus Foundation postdoctoral research fellowship (SEH)
Wellcome Trust Investigator Award (107116/Z/15/Z) (GS)
UK Dementia Research Institute Foundation award (UKDRI-1005) (GS)
Alzheimer’s Research UK senior fellowship (TL)
Alzheimers Society (AG)
UKRI Future Leaders Fellowship (MR/T042184/1) (MS)
Author contributions:
Conceptualization: ALB,OGW,MJK,SEH,JH,MEW,PF
Data curation: ALB,OGW,MZ,SBS
Formal analysis: ALB,OGW,MJK,MZ,SBS,AB
Funding acquisition: PF,MEW,EB
Investigation: ALB,OGW,MJK,SEH,MZ,FCYL,LM,YAQ,SBS,AB,WCL,AG
Methodology: ALB,OGW,MJK,SEH,JH,MEW,PF
Project administration: PF,MEW
Resources: HP,TL,EB
Software: ALB,OGW,MZ,SBS,JH
Supervision: PF,MEW,JH,JU,MS,TR,TL,EMCF,GS
Visualization: ALB,OGW,MJK,WCL
Writing – original draft: ALB,OGW,MJK,MEW,PF
Writing – review & editing: SEH,WCL,EB,JU,JH
Competing interests:
ALB, OGW, MJK, SEH, MEW and PF declare competing financial interest. A patent application related to this work has been filed.
Data and materials availability:
Analysis code and data to reproduce figures available: https://github.com/frattalab/unc13a_cryptic_splicing/
RNA-Seq Data for i3Neurons, SH-SY5Y and SK-N-DZa are available through the European Nucleotide Archive (ENA) under accession PRJEB42763.
Public data was obtained from Gene Expression Omnibus (GEO): iPSC MNs (Klim et al., 2019)-GSE121569, SK-N-DZb-GSE97262, and FACS-sorted frontal cortex neuronal nuclei-GSE126543.
Riboseq: E-MTAB-10235.
Targeted RNA seq: E-MTAB-10237
Minigene iCLIP: E-MTAB-10297
NYGC ALS Consortium RNA-seq: RNA-Seq data generated through the NYGC ALS Consortium in this study can be accessed via the NCBI’s GEO database (GEO GSE137810, GSE124439, GSE116622, and GSE153960). All RNA-Seq data generated by the NYGC ALS Consortium are made immediately available to all members of the Consortium and with other consortia with whom we have a reciprocal sharing arrangement. To request immediate access to new and ongoing data generated by the NYGC ALS Consortium and for samples provided through the Target ALS Postmortem Core, complete a genetic data request form at [email protected].
NYGC ALS Consortium Whole Genome Seq: to be released later with companion manuscript.