Jun
07

In Silico Modeling of ALS-FTD: Choosing the Biochemical Path(way)

Happy Friday! The first week and a half of summer research have been chock-full of information as I read previous studies in the literature and try to piece together errant pathways from exciting gene databases and benchwork results. As I grow increasingly immersed in the shifting landscape of molecular and biochemical research, I must constantly remind myself to see the big picture: how do amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD) develop and progress in the body? As well exhibited in the graphic below, there seem to be a thousand and one possible pathways that light the fire and initiate the disease (aka the pathogenesis). And while it is certainly possible (and pretty likely) that several different problems lead to the same issue(s), I’m searching for some underlying themes that connect these cases of life-altering disease.

An overview of potential disease mechanisms in ALS. From the 2017 paper, Modeling amyotrophic lateral sclerosis: progress and possibilities, by Van Damme et al.

An overview of potential disease mechanisms in ALS. From the 2017 paper, “Modeling amyotrophic lateral sclerosis: progress and possibilities,” by Van Damme et al.

In my search for problems consistent across cases of ALS-FTD, I’ve started with a major hallmark of ALS-FTD: the protein TAR-DNA Binding Protein-43 (TDP-43). While typical, healthy cells maintain a much higher ratio of this protein in the nucleus, affected cells often present clumps of TDP-43 in the cytoplasm. While this impairment may not represent the original source of the problem, these TDP-43 aggregates seem to be the most widespread link between cases of ALS-FTD, so I branched out from this problem to find pathways in the cell that might affect or be affected by these aggregates. From there, I am continuing to search for the central pathway upon which my model will focus. I will hopefully cap off the week today with some possible sketches of pathways implicated in the transport of molecules between the nucleus and cytoplasm, and will scour a few more databases looking for more information on TDP-43 functions.

Bonus excitement for today: lab lunch together!

Have a wonderful weekend!

Comments

  1. amrader says:

    Hi Aaron,

    Thank you so much for your interest and kind words! One more technical but (I think) intriguing insight that came from the the literature in 2018 was evidence from Ederle et al. and Pinarbasi et al. that the TDP-43 protein diffuses through the nuclear membrane into the cytoplasm rather than being actively exported using via its Nuclear Export Signal (NES) (which TDP-43 purportedly has in its sequence). While this may not sound terribly exciting, I mentioned in my post the relevance of nuclear transport to understanding the mechanisms at play in ALS-FTD, and this finding certainly shakes a few ideas that I believe a good deal of the research community was building upon. In fact, research has been done on an inhibitor of proteins that help TDP-43 exit the nucleus actively, which could potentially be used therapeutically (although these findings seem to suggest that this inhibitor does not target the real issue). If you’re interested in reading more, this article explains the findings more in detail in an accessible forum style: https://www.alzforum.org/news/research-news/no-tdp-43-and-fus-are-not-actively-exported-nucleus.

    Thanks again for your comment! Have a wonderful week!

  2. achiggins says:

    Hi Anna,

    I’m amazed at your drive to stitch together a coherent understanding of TDP-43’s qualities and performance! It’s not wonder that the nature and progress of ALS still eludes a lot of the scientific community, when there can be so many possible initiators of the disease. On that note, the image you shared was very informative. Although realizing the versatile nature of diseases is more than a tad bit morbid, it’ll no doubt help you and other researchers piece together a guide to possibly fighting them, one day. Since you’ve been going over scholarly literature recently, I am curious about the most interesting or thought-provoking discovery you’ve discovered, from reading others’ research on the topic. Has anything caught your eye?

    Best of luck finding the pathway you think is most germane to your research interests. (And have a great lunch!)

    Sincerely, Aaron

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