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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...
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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 Walker |
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Have 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. View all comments by Roxanne Ol |
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