Sephton CF, Cenik C, Kucukural A, Dammer EB, Cenik B, Han Y, Dewey CM, Roth FP, Herz J, Peng J, Moore MJ, Yu G. Identification of neuronal RNA targets of TDP-43-containing ribonucleoprotein complexes. J Biol Chem. 2011 Jan 14;286(2):1204-15. PubMed.
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Northwestern University Feinberg School of Medicine
This paper by Gang Yu and colleagues describes a very interesting study to identify the set of RNAs that bind to TDP-43, a protein that has been implicated in a wide range of neurodegenerative diseases. The authors performed an unbiased screen of TDP-43 RNA targets and found over 4,000 RNAs that were bound to TDP-43. The TDP-43-binding RNAs had diverse physiological roles, primarily involving synaptic function, RNA metabolism, and neuronal development. Importantly, several RNAs involved in neurodegeneration were identified, including those for TDP-43 itself, FUS/TLS, progranulin, tau, APP, synuclein, Cdk5, huntingtin, presenilin, PrP, sirtuin, SOD, TAR DNA binding protein, and ataxin1 and 2.
This study is an important advance in the field and represents a first step toward a comprehensive understanding of the biological functions of TDP-43 and how this RNA binding protein is involved in neurodegenerative disease. It appears from the present study that the physiological functions of TDP-43 are quite wide and involve numerous diverse RNAs in neurons. Additional experiments will be required to fully validate the current results, but the present findings are fascinating and encouraging. Although it is not yet clear as to the level that the authors' results may inform about novel therapeutic approaches for neurodegenerative diseases, the hope is that the information provided in this study will help move toward the identification of novel targets of future drugs for the treatment or prevention of neurodegeneration.
Emory University
Two prominent messages emerge from the Sephton paper and the burgeoning literature on TDP-43: 1) TDP-43 is important for the normal functioning of cells; and 2) its actions are many and complex. This being so, is it realistic to assume that targeting one or a few of its ~4,000 interacting partners could effectively modify the course of TDP-43 proteinopathies such as ALS and FTLD?
Maybe, but perhaps the most parsimonious target—the bull’s eye, to keep with the theme—is the same as in other neurodegenerative diseases: the seeded accumulation of the protein in the wrong place. If a normally folded TDP-43 molecule encounters a corrupted conformational variant of the protein (or possibly some other seed) outside the nucleus, the normal protein could itself become corrupted, aggregation-prone, and unable to re-enter the nucleus in its biologically active form. In addition to impairing the function of multiple RNA pathways, TDP-43 aggregates might also be transferred to other cells via normal cellular transport, release, and uptake mechanisms, thereby disseminating the disease from one region of the nervous system to another.
If this scenario is correct, then the most direct therapeutic objective for the TDP-43 proteinopathies would be to hinder the formation of proteinaceous seeds, promote their disposal, or block their interactions with normally folded TDP-43 molecules. In short, RNA mismanagement appears to be the proximal cause of cellular dysfunction in these disorders, but the problem originates with the seeded sequestration of TDP-43 in a form that renders it unable to perform its normal duties.
View all comments by Lary WalkerHave you heard of Significance Analysis of Interactome (SAINT) (Choi et al., 2010)? It will allow researchers globally to quickly assess the reliability and accuracy of protein binding data helping to further their studies of cancer and other illnesses.
References:
Choi H, Larsen B, Lin ZY, Breitkreutz A, Mellacheruvu D, Fermin D, Qin ZS, Tyers M, Gingras AC, Nesvizhskii AI. SAINT: probabilistic scoring of affinity purification-mass spectrometry data. Nat Methods. 2011 Jan;8(1):70-3. PubMed.
View all comments by Roxanne OlThis is interesting, especially the viral genome theories.
References:
View all comments by Ian RobertsMartin.
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