PANEL DISCUSSION - MECHANISMS TO MEDICINES FOR PATIENTS

Transcript

• 00:01Hello.
• 00:02So when you knock out,
• 00:05the DNA j c six,
• 00:07do you,
• 00:08do you see with, I'm
• 00:10not sure you ever performed
• 00:11a spatial transformers or any
• 00:13spatial photonics
• 00:15technology to the knockout mouse,
• 00:17see where where this knockout
• 00:19effect,
• 00:20happened in which part of
• 00:21the body or with part
• 00:22of the brain middle brain?
• 00:24So it's a conventional knockout.
• 00:26So it's in knocked out
• 00:27in all
• 00:28parts of the body.
• 00:30We have done proteomics
• 00:32on the brain.
• 00:34We also have done proteomics
• 00:36on synaptic turtles and in
• 00:38this vesicle
• 00:39fraction.
• 00:40What we see even in
• 00:41the brain, even though it's
• 00:42a whole body knockout,
• 00:44is there dopenergic selective,
• 00:47effects. So the pathways are
• 00:49all dopenergic even though it's
• 00:51a whole brain knockout. And
• 00:53I think we think in
• 00:54part because of the biology
• 00:56of dopamine and dopamine transporter
• 00:59that
• 00:59that even though this is
• 01:01occurring in all synapses, they
• 01:02are preferentially
• 01:04one.
• 01:07But maybe those, latest technology
• 01:09and spatial transforms can also
• 01:11measure be used to see
• 01:12other genes, not just DNA
• 01:14t six itself, but other
• 01:15genes That's great. That's great.
• 01:17That is correct. You couldn't
• 01:18we've just done mainly proteomic.
• 01:20We have not done.
• 01:25Other questions? I know it's
• 01:26been a long day.
• 01:29Steve.
• 01:31As a question of Pietro,
• 01:36with regard to lysosomal
• 01:38fragility
• 01:39and Parkinson's,
• 01:41is there any reason to
• 01:42think the nigrostriatal
• 01:43system would be particularly
• 01:45sensitive?
• 01:46For mitochondrial genes, there's been
• 01:47a lot of, you know,
• 01:49thought that dopamine makes them
• 01:51more sensitive to
• 01:53oxidation. But for lysosomes, is
• 01:55there some reason to think
• 01:56that this pathway
• 01:58would be more sensitive?
• 02:00It's a good question.
• 02:02There is
• 02:03cannot imagine why the dopaminergic
• 02:05system, they should be more
• 02:06fragile.
• 02:08I tend to believe, however,
• 02:09that this fragility is particularly
• 02:12important in microglia cells
• 02:14because some of these Parkinson's
• 02:16disease protein are highest pressing
• 02:18microglia cells. We find VB13
• 02:20c is higher in microglia
• 02:22cell.
• 02:23Sean is working on our
• 02:24two. We find this go
• 02:25up in microglia.
• 02:27And so there might be
• 02:28something in microglial cell, which
• 02:30then
• 02:31transform a neuroinflammation,
• 02:33etcetera, if you don't if
• 02:35you have, dysplagility.
• 02:41I also have a question
• 02:42for Pietro. Yeah. So you
• 02:44referred to the sequential recruitment
• 02:46of BPS thirteen c and
• 02:48LURK two.
• 02:50Do you have any data
• 02:51that
• 02:52the LURK two recruitment depends
• 02:53on BPS thirty c thirteen
• 02:55c? And is there in
• 02:57any data from human genetics
• 02:59that show that, mutations in
• 03:01BPS thirteen c alters susceptibility
• 03:04to LURK two mutations?
• 03:07I cannot comment on the
• 03:09genetic data. As far as
• 03:10I know, there is no
• 03:11evidence.
• 03:13Yeah. The so we know
• 03:15for sure the VP of
• 03:16thirteen c is recruited
• 03:18really in thirty second is
• 03:19already there, and then it
• 03:21goes up and goes up
• 03:22very rapidly.
• 03:23LRR two is much delayed,
• 03:26and, Sean has shown very
• 03:27nicely that is dependent on
• 03:29CASM, and CASM seems to
• 03:31be delayed.
• 03:32We are trying to investigate
• 03:34whether there is a potential
• 03:35relationship. I told you that
• 03:37if you don't have a
• 03:38V13 in in in inactivation
• 03:40of innate immunity,
• 03:42shown that innate immunity is
• 03:43upstream of CASM. So there
• 03:45are potential
• 03:46interrelationship,
• 03:48which are very interesting.
• 03:52Yeah. I have a question,
• 03:54regarding,
• 03:55alpha synuclein pathology
• 03:57in patients. Sometimes,
• 03:59the disease is localized in
• 04:00certain areas in other types
• 04:03of PD such as, the
• 04:04case of VPS thirteen c
• 04:06is very diffusely
• 04:08accumulated in the brain. Is
• 04:09there any,
• 04:10insights of why
• 04:12a disease can be widespread
• 04:14or localized?
• 04:18I wish I had answers
• 04:19to this.
• 04:20I wish I had answers
• 04:21to these questions.
• 04:23The protein is sort of
• 04:25ubiquitously
• 04:26expressed in the brain, so
• 04:27there is not something that
• 04:29will explain.
• 04:30The idea is that maybe
• 04:31it's templated like Steve said
• 04:33in certain regions,
• 04:36sort of corresponding to Brock's
• 04:38staging. But, overall, that's a
• 04:41sort of this question of
• 04:42regional vulnerability
• 04:44is a
• 04:45question that's complex with us
• 04:47all, not just in Parkinson's,
• 04:49but in all neurodegenerative.
• 04:55Can I ask Pietro a
• 04:57question? Okay. Sure.
• 04:59So the the you said
• 05:01this is sort of an
• 05:03interplay between lysophagy
• 05:05and repair.
• 05:07And so
• 05:08how is that
• 05:10sort of
• 05:11balance or point that point,
• 05:13regulate?
• 05:15Yeah. First of all, I'm
• 05:16not sure whether it's correct
• 05:17to say balance. It is
• 05:19either or. You know? It's
• 05:20just too much damage to
• 05:21go to isophagy.
• 05:22And,
• 05:25yeah, I don't I don't
• 05:26have a good answer. I
• 05:27guess if it's eventually, it
• 05:28doesn't repair,
• 05:31it goes into the Do
• 05:32you see that?
• 05:33Do you see that? If
• 05:34you don't repair,
• 05:36I see Yes. For sure.
• 05:37There is.
• 05:38No. No. No. There is.
• 05:39But if you don't repair,
• 05:40are you moving the balance?
• 05:44I I I I let's
• 05:46say, I don't have experiment
• 05:47to show that
• 05:48since there is lysophagy and
• 05:50there is repair,
• 05:52I assume that it's either
• 05:53or. But we we never
• 05:54really look into that
• 05:56direct. Good point.
• 05:59I guess that raises the
• 06:00question. Is
• 06:02lysosomal
• 06:03repair
• 06:05a
• 06:07an an interesting therapeutic target
• 06:09in your mind for Parkinson's
• 06:11disease? Yeah. I thought a
• 06:12lot about this, and
• 06:16I cannot imagine
• 06:18I mean, I find I
• 06:20would find very difficult to
• 06:21think that we could find
• 06:22a way
• 06:23to repair lysosome with the
• 06:25magic bullet. I think, however,
• 06:28these data suggest that anything
• 06:29you can do to avoid
• 06:31lysosomal damage
• 06:32can be beneficial.
• 06:34And so you can imagine
• 06:36that environmental
• 06:37factor
• 06:38that affect lysosome biology,
• 06:40including defection diseases, etcetera,
• 06:44may
• 06:44result in damage of lysosome.
• 06:46So I think
• 06:47with the the kind of
• 06:49data I showed
• 06:50suggest more than what we
• 06:52have to think about is
• 06:53how can we avoid lysosomal
• 06:54damage
• 06:55rather than think that we
• 06:56have a a a pill
• 06:58that you
• 07:00that you could take and
• 07:01then you'll you'll rescue your
• 07:02lysosome. Yeah.
• 07:06Sean? Floor, is there go
• 07:08ahead.
• 07:09I should be thinking a
• 07:10lot about this question. So
• 07:12Mhmm. Yeah. So my my
• 07:14comment on that question was
• 07:17the
• 07:18I'm very curious about what's
• 07:20gonna happen,
• 07:22with ongoing clinical trials related
• 07:24to LRRK two inhibitors or
• 07:26just further development of that
• 07:28pathway because in looking at,
• 07:30first, how LRRK two,
• 07:33mutations
• 07:34what they're doing to lysosomes
• 07:36as Pietro showed there with
• 07:38the VBS thirteen c. More
• 07:40LRRK two kinase activity makes
• 07:42lysosomes
• 07:43apparent seems to be more
• 07:44fragile.
• 07:45And when we genetically deplete
• 07:47it or pharmacologically
• 07:48inhibit
• 07:49by various measures in a
• 07:50dish, the lysosomes
• 07:52look better.
• 07:53And so there may be
• 07:54opportunities there for LRRK two
• 07:56inhibition to make lysosomes, if
• 07:58not, more repairable, but more
• 08:00durable in the first place.
• 08:04Thank you. And I guess
• 08:05on that note,
• 08:07our time is up.