TAR DNA-binding protein 43

Today we're talking about a form of dementia that many people have never heard of, even though it may account for some memory loss in very old adults and can look a great deal like Alzheimer's disease.

It is typically called limbic predominant age-related TDP-43 encephalopathy.

That is a mouthful to say, so for the rest of this episode, we'll just call it by its abbreviation, L-A-T-E, or LATE.

Our title for the episode today is Late, the dementia that can look like Alzheimer's.

It could be amyloid or tau in Alzheimer's disease.

It could be TDP-43 in motor neuron disease or amyotrophic lateral sclerosis, ALS.

So the initiators can be very different but there is not a possibility, I strongly feel, I just do the math in my head on this, there is not a possibility that each one of those cells responds differently to every single stimuli because there's an infinite number of stimuli in the universe and there is not an infinite number of combinations of genes to give us an infinite number of responses in glia and microglia and astrocytes.

So there's a smaller number of responses that they have I would say arguably more in microglia than there are in astrocytes.

And then also, you know, we're talking about Parkinson's a lot here.

It could be pathogenic proteins as well.

So alpha-synuclein, of course, is a big one in Alzheimer's disease or it could be amyloid or tau in Alzheimer's disease or it could be TDP-43, another protein that's important in pathogenesis of ALS or motor neuron disease.

So there are many different things that we think could make them susceptible.

So I won't, I won't say anything more than that because you gotta attend the meeting to hear about the details, but that will be shared during that-- during the annual meeting as well.

You mentioned a little bit about what does the future look like, and I, I would say that The, first of all, excitingly, I think we have really good targets, so we- and we're really understanding much more about pathways, particularly t- those related to sporadic ALS and TDP-43 mediated pathways, as well as those other genes we mentioned, FUS and SOD1, that really allow us now more so than ever to really understand relevant pathways and target those relevant pathways.

And I think we're seeing that as, as several groups of pharma start to have additive information regarding those.

And I think we'll also be leveraging much more so than ever, and I know sitting on the scientific advisory board, uh, as, as both Dr. Andrews and I do, we've really seen this emphasis on biomarkers, and can we leverage biomarkers to speed trials to really understand targets and target engagement? Uh, so I, I really think that's, that's really, I would view, at least the next few years, getting bett- better biomarkers and, and really, um, leveraging opportunities to influence those pathways.

Yeah.

So some of the new science now is trying to target antisense oligonucleotides and viral vectors towards these kind of modifier genes in sporadic ALS, um, or even targeting SOD1.

So we have several early phase clinical trials targeting UNC13A, STATHMIN2, SOD1, um, and TDP-43, and so there are, um, phase one studies underway, and so this is kind of the new, the new wave of the future, and that will be an exciting time for sporadic, um, ALS, especially for those dealing with that type of, um, ALS 'cause it's, it's-- they see so much of the success that's happening for the smaller proportions of people who carry the SOD1 and now FUS-associated ALS.

[upbeat music] We're going to take a quick break from our conversation with Dr. Maragakis and Dr. Andrews to keep you up to date on the latest developments in neurology.

So the problem is, is that SOD1 represents 2% of ALS, right? So not good enough.

That's, [laughs] that's not most people I see in clinic, right? So can we apply the logic of what causes ALS in sporadic disease? The common element that we have, um, is this protein called TDP-43, which was actually the aggregation of TDP-43, uh, is seen in 97% of people with ALS.

Um, and that was actually discovered at Penn, uh, quite a while ago.

Um, and at first it's just like, okay, there's some phosphorylated TDP-43 in these cells.

We have no idea does that matter.

Like what, what's the relevance of this? And in most, um, neurodegenerative conditions, there are aggregated proteins, meaning that there's clumps of some protein, amyloid, tau.

And what's interesting in ALS is that TDP-43 isn't just clumped up.

It's also because it's clumped up in the cytoplasm, in the body of the cell and not in the, in the nucleus, the brain of the cell.

So tau is the main one, but some cases can have other proteins.

One is called TDP-43.

There are some frontal temporal dementias that, and motor neuron diseases that, that are, that can have this protein too, but for some reason, some cases can have some TDP, uh, aggregation.

It's another protein that can get dysregulated and stick, become sticky.