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Identification of Neuronal RNA Targets of TDP-43-containing Ribonucleoprotein Complexes
Open accessAbstract
TAR DNA-binding protein 43 (TDP-43) is associated with a spectrum of neurodegenerative diseases. Although TDP-43 resembles heterogeneous nuclear ribonucleoproteins, its RNA targets and physiological protein partners remain unknown. Here we identify RNA targets of TDP-43 from cortical neurons by RNA immunoprecipitation followed by deep sequencing (RIP-seq). The canonical TDP-43 binding site (TG)(n) is 55.1-fold enriched, and moreover, a variant with adenine in the middle, (TG)(n)TA(TG)(m), is highly abundant among reads in our TDP-43 RIP-seq library. TDP-43 RNA targets can be divided into three different groups: those primarily binding in introns, in exons, and across both introns and exons. TDP-43 RNA targets are particularly enriched for Gene Ontology terms related to synaptic function, RNA metabolism, and neuronal development. Furthermore, TDP-43 binds to a number of RNAs encoding for proteins implicated in neurodegeneration, including TDP-43 itself, FUS/TLS, progranulin, Tau, and ataxin 1 and -2. We also identify 25 proteins that co-purify with TDP-43 from rodent brain nuclear extracts. Prominent among them are nuclear proteins involved in pre-mRNA splicing and RNA stability and transport. Also notable are two neuron-enriched proteins, methyl CpG-binding protein 2 and polypyrimidine tract-binding protein 2 (PTBP2). A PTBP2 consensus RNA binding motif is enriched in the TDP-43 RIP-seq library, suggesting that PTBP2 may co-regulate TDP-43 RNA targets. This work thus reveals the protein and RNA components of the TDP-43-containing ribonucleoprotein complexes and provides a framework for understanding how dysregulation of TDP-43 in RNA metabolism contributes to neurodegeneration.
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Metadata
- Authors
- Sephton, C. F., Cenik, C., Kucukural, A., Dammer, E. B., Cenik, B., Han, Y., Dewey, C. M., Roth, F. P., Herz, J., Peng, J., Moore, M. J., & Yu, G.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-01
- Volume
- 286
- Issue
- 2
- Pages
- 1204-1215
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1967443709
- Cited by
- 434
- References
- 50
- FWCI
- 20.66
- Type
- journal article
- Language
- en
- Open access
- hybrid
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