Search For A Self Cure 
 

Welcome! Now we are going to talk about TDP-43. It’s really funny, my husband went to an ALS conference with me and he is not a scientist and he was like “Yentli, what is this DP-4 protein they keep talking about?” and I was like “what are you talking about” and he was like “D…T…TD??” and I was like “OHHHHH TDP-43!!” It’s really important and a lot of treatments are really focused on this for C9orf72 ALS and FTD but also several other genetic forms. So, what does TDP-43 do and why do we care so much about it? Well, in a separate video, I will explain about this loss-of-function and gain-of-function hypothesis. But, in order for you to understand what happens when we lose TDP-43 function in the nucleus, you need to understand what it does. 

 

Part 1: Biology 101
To understand TDP-43, you need to understand the central dogma of molecular biology: DNA to RNA to protein. DNA is the blueprint that you would that you would hold in a safe and the safe is a nucleus. RNA is the intermediate blueprint that you would take out of the safe that you could use and that you could make copies of. Proteins are the buildings that you are making in the city that is the cell, in a factory, that really allows you to do everything that the cell is able to do. Cells work together in unison to make tissues and tissues make organ. And Ta-Da! You have a whole human being. 

 

TDP-43 is an alternative splicing factor. What that means (and this is kind of mind boggling!) is that DNA does not just go to one RNA and then to one protein. The RNA can be cut up into different versions (called alternative transcripts) that can then make unique proteins, each with a different function. So, it’s not just a straight line of one DNA to one RNA to one protein every time. Instead, it’s DNA to different versions of RNA, each of which then encode a different version of the protein. That means that many different types of protein (buildings) can be made from the same DNA/genetic material (blueprint). This is what allows our genome to be relatively small for all that it can do! This is why TDP-43 is so important to making a bunch of buildings in our cell function normally. 

 

What happens when TDP-43 isn’t working in the cell? We think this is really important in contributing to ALS. There are a lot of proteins (buildings) that are essential in the city of our cell that are not getting made. And when the buildings are not getting made and are not functioning properly in a neuron, neurons (which are pretty flimsy) start to die. Thus, TDP-43 contributes to loss-of-function in and has implications for biomarkers and therapeutics. Our scientists are working on both. 

 

Part 2: Biomarkers
Not only does TDP-43 function in the nucleus to make different proteins, or buildings. When it’s not working properly in the nucleus, you can get really weird buildings that you shouldn’t be making. Let’s say a neuron should not have an amusement park. It should have a post-office and a hospital. Well, obviously, it’s bad if the post-office and hospital aren’t made, But, if there is an amusement park where the hospital should be? We can try to detect that amusement park to say, “THAT neuron doesn’t have TDP-43 inside working!” So, if you do that, you’re detecting a signal that implies that TDP-43 has loss-of-function in that cell. And that is what we call a biomarker. You can develop [biomarkers] to try to predict which people will get disease later. You can use [biomarkers] to test if you have corrected TDP-43 function in a cell. This has a lot of implications.

 

Part 3: Therapeutics
Understanding the loss-of-function of TDP-43 in a cell is also important to understand therapies being used to target it. Some people are working to prevent TDP-43 from creating clumps in the cytosol and ushering it back into the nucleus so it can do its job. This would target both gain-of-function and loss-of-function. Meanwhile, some people are trying to replenish the TDP-43 that is being lost and putting a good/corrected copy that can’t gunk up outside the nucleus and wreak havoc inside the cell. Dr. Phil Wong is talking about that [in a later video]. 

Thank you for listening and I hope to catch you up on key principles of molecular biology in future videos. You can reach out to End the Legacy if there are any topics in particular you would like to learn about. And, if there are any experts in particular you would like me to interview, please reach out! Bye!

Bonus Information!
TDP-43 is implicated in different parts of the motor neuron in SOD1-ALS – this is an active area of investigation!
Motor neurons go from our head to the level of the spinal cord where their target muscle is – these are really long neurons which makes them extra susceptible to insult.
TDP-43 beyond ALS/FTD – Recent studies have shown that TDP-43 may also play a role in Alzheimer’s disease (and is present in 57% of cases). Additionally, traumatic brain injury has been shown to cause dysfunction of TDP-43, leading to accelerated neurodegeneration. Thus, therapeutic work focused on TDP-43 may have broader implications and benefit individuals not just with ALS/FTD but also other forms of neurodegeneration.