LRRK2 pathways in PD | Congress 2026

[00:00:37] Tiago Outeiro: Of course. It's great to have more basic scientists like me on the podcast. That's not often the case, but it's great that we can represent basic science in the Congress. And so I want to start by asking you to give us a brief summary of what you talked about in your presentation during the Congress.

[00:00:53] Sabine Hilfiker: Basically I covered LRRK from its discovery, genetic variants that have been described across the world, to slight differences in alpha-synuclein pathology and SAA assays and what they could mean to cell biology and molecular mechanisms, which is really what I'm most interested in. There's been a lot done with LRRK in terms of mechanisms.

LRRK is involved in autophagy, in lysosome damage. There is effects on mitochondria, and there is effects on cilia and centrosomes and trying to give an update on recent results on what it could mean to have cilia and cohesion, centriole cohesion deficits, for biomarkers as well as physiology and pathophysiology.

[00:01:45] Tiago Outeiro: So you were able to fit almost everything we know about LRRK in your presentation, which is great. But we still don't fully understand what the problem is with LRRK. So we know it is a kinase, so an enzyme that phosphorylates proteins. Initially, it was found as a kinase that would phosphorylate itself. But then a few years later, we found that it phosphorylates some proteins called Rab proteins.

So why do we think this is important for LRRK biology?

[00:02:13] Sabine Hilfiker: So yeah, I do think that has been a critical discovery, by Dario Alessi and Matthias Mann, of a subset of these Rab proteins being phosphorylated by LRRK. Rab proteins really are master regulators of membrane trafficking. They confer identity to different organelles. They're required for vesicles to bud from an organelle, to be trafficked, docked at the target membrane, and then fuse.

So, without Rab proteins, you would have chaos in terms of intracellular specificity. There's only a subset of Rab proteins that are phosphorylated by LRRK. We do still not understand why that is. When these Rab proteins are phosphorylated, it's clear that you get a loss of function in terms of membrane trafficking.

But remember, mutations in LRRK are autosomal dominant. And again, Dario Alessi and Suzanne Pfeffer have shown that when these Rab proteins are phosphorylated, they gain a new ability to bind to a very small subset of proteins. And that gives you a dominant toxic gain-of-function phenotype that's related to cilia loss and effects on centriole cohesion.

And we think that is a critical cell biological consequence of LRRK.

[00:03:35] Tiago Outeiro: This is complex biology we're talking about, so it's not easy for all our listeners to understand and for me either. I'm trying to also understand what's going on, but it's not so easy.

But what we know is that alpha-synuclein is a protein that is phosphorylated on serine-129, and we use this often as a marker of pathology. So do we think LRRK2 phosphorylates synuclein or not? What is the data showing us?

[00:03:58] Sabine Hilfiker: I think there's no clear evidence that LRRK phosphorylates synuclein. It's been really important in the literature when it was shown that about 30% of LRRK PD patients, by seed amplification assay, don't have positivity in the CSF, and that correlates with about 30% of LRRK PD patients also not having Lewy body pathology postmortem.

And that kind of raised the issue, is LRRK PD alpha-synuclein independent? And I think recent data have shown that even in the absence of Lewy body pathology, you do have alpha-synuclein oligomers in the brain. So, maybe alpha-synuclein pathology in LRRK PD is something that's happening downstream from LRRK, but it's not alpha-synuclein independent.

So I think that's very interesting to pursue.

[00:04:55] Tiago Outeiro: Yeah, and those studies that you alluded to from last year were really interesting because they were using a different technique that, although we don't see the typical Lewy bodies, we see alterations in alpha-synuclein, but we still don't know if there's a direct connection with the LRRK2 increased activity.

[00:05:11] Sabine Hilfiker: Exactly. We don't.

[00:05:13] Tiago Outeiro: And we know LRRK is expressed in many different cell types, including neurons and immune cells. How important do you think non-neuronal cells, particularly microglia and other myeloid cells, are in LRRK2-associated Parkinson's disease?

[00:05:30] Sabine Hilfiker: I think that's an important question, and I think they're going to turn out to be really important. Again, from a biomarker perspective, LRRK is known to have impact on lysosomes. You get lysosomal exocytosis. If that comes from microglia, if there's a microglia signature that can be detected in CSF, that will be a very good biomarker for stratifying LRRK PD patients from non-LRRK PD patients.

[00:05:56] Tiago Outeiro: And of course, one major goal has been to try to affect this hyperactivity of LRRK2 using inhibitors. There were different inhibitors tested already in clinical trials. So can you tell us a little bit about what was the idea behind, what were the molecules trying to do, and what were the results that we obtained so far?

[00:06:18] Sabine Hilfiker: Yeah. So I think there has been a lot of hype about the latest Biogen Denali phase 2B clinical trial results. They showed lack of beneficial effect. Again, that's not a failure, I would say. Negative results are an opportunity to learn. This was a very well-designed clinical trial. They had target engagement biomarkers.

It was a relatively large patient cohort of early PD patients. Again, you could argue we don't know how much of LRRK in the brain needs to be inhibited, so their CSF biomarker suggests about 30% of LRRK was inhibited in the brain. That may not be enough. It may have been too late. One may have to inhibit LRRK earlier, even at the prodromal stage.

Maybe the measurement of UPDRS combined II and III scores is too broad. Maybe one has to go with more subtle measurements with digital biomarkers, et cetera. So I think there's a lot we can learn from this very well-designed clinical trial. There are other approaches ongoing. One is by Arvinas, and they have late-breaking abstracts here.

That's a PROTAC-mediated approach, trying to degrade LRRK rather than inhibiting with a type 1 inhibitor. There's a clinical trial going on from Neuron23. They use another type 1 kinase inhibitor. They use digital biomarkers, and importantly, they aim to stratify or enrich patients whose Parkinson's may be LRRK-driven.

And I think that is what kind of was missing in the LUMA trial from Biogen Denali.

[00:08:03] Tiago Outeiro: There's still a lot to be excited about.

[00:08:06] Sabine Hilfiker: There's a lot to be excited about, absolutely. I'm very positive about these trials having positive effects. I think they need to be modified in a way, and we're learning as we're going on. There is other companies.

There was a late-breaking abstract from Brenig Therapeutics. Again, they have another LRRK inhibitor that seems to be enriched in the brain, or by their formulation, and they show like a 60% decrease in LRRK levels in the CSF. So there's so many different approaches out there, and I think if they implement a patient enrichment, we may well see positive results coming out in the near future.

[00:08:47] Tiago Outeiro: We'll have to look forward to those results from the trials. But, as a cell biologist, so as a basic scientist, what would you like to learn in the next 5 years about LRRK biology that you think may bring new light into the connection between LRRK2 mutations and Parkinson's disease?

[00:09:06] Sabine Hilfiker: I think we've looked at many different places, leaving no stone unturned as Dario Alessi would say, and I think that's important. But I'm excited about going back to preclinical animal model systems. So the lab of Loukia Parisiadou, and Raj Awatramani and Daniel Dombeck, they had a really impactful paper recently showing that you get a decrease in dopamine release, specifically in the vulnerable neurons in the LRRK knock-in mouse model, and they could measure that in live, moving mice.

Going back to these models and saying, "Is a LRRK inhibitor able to revert that?" Suzanne Pfeffer's data showing that 3 months LRRK kinase inhibitor reverts the ciliary loss in the cholinergic interneurons in the striatum. How does that affect cholinergic prodromal phenotypes that we see in these animal models?

I think going back to these preclinical models and really understanding what a LRRK inhibitor or LRRK-modifying therapy can do is going to give us greater confidence to go back into the clinical trial. So that, to me, is one of the key gaps in knowledge that need to be filled.

[00:10:20] Tiago Outeiro: Great. Fantastic. I think this was very informative. We covered a lot of ground, so thank you so much, Sabine, for your time and for talking to us for the podcast.

[00:10:29] Sabine Hilfiker: It was a pleasure. Thank you, Tiago.

[00:10:31] Tiago Outeiro: Thank you all for listening, and join us in our upcoming podcasts.