SYNAPTIC DYSFUNCTION IN PARKINSONS DISEASE

Transcript

• 00:00Our next speaker is Sringangachandra,
• 00:05professor
• 00:05in the department of neurology
• 00:07and neuroscience,
• 00:09and she previously trained with
• 00:11Nobel laureate,
• 00:13doctor Tom Sudhoff, and received
• 00:15a PhD actually in chemistry
• 00:18of from Purdue University.
• 00:21Srikanga?
• 00:24Can I just probably take
• 00:25this part back?
• 00:28One of the part back.
• 00:29Right? Are you guys gonna
• 00:30need them? Can you hear
• 00:31me? Okay. So I'd like
• 00:33to begin by thanking and
• 00:35congratulating
• 00:36Clemons on sort of kick
• 00:38starting the Adams and recruiting
• 00:39all
• 00:40faculty. So I'm gonna tell
• 00:42you about synaptic dysfunction in
• 00:44Parkinson's disease.
• 00:47As all of you know,
• 00:48the two hallmarks of the
• 00:50disease are
• 00:54are are the death of
• 00:56neurons in the nigra that
• 00:58project,
• 00:59to the put putamen in
• 01:00the cortex.
• 01:01And as you already heard,
• 01:04Lewy body pathology, which is
• 01:06characterized by this characteristic
• 01:08phosphorylation that's serine one twenty
• 01:10nine.
• 01:11So, the other feature of,
• 01:14sort of early Parkinson's disease
• 01:16is not just,
• 01:17the death of neurons and
• 01:18pathology,
• 01:19but also
• 01:21the dying back of these
• 01:23dopenergic
• 01:23synapses,
• 01:25at the striatum. And this
• 01:26is such a sort of
• 01:28profound and striking,
• 01:30phenotype. It is used clinically
• 01:33to diagnose,
• 01:34early Parkinson's. So as soon
• 01:35as you're diagnosed, you you
• 01:37are,
• 01:38you know, you get imaging,
• 01:39and this is a way
• 01:40of determining for sure that
• 01:41you have Parkinson's.
• 01:43And so, traditionally,
• 01:45what has been oh, sorry.
• 01:47Traditionally, what has been used
• 01:49is
• 01:49f eighteen dopa, which is
• 01:51the precursor for dopamine.
• 01:53And, as,
• 01:55dopa is then converted to
• 01:57dopamine
• 01:57and then packaged into synaptic
• 01:59vesicles by the vesicular monoamine
• 02:02transporter, VMAT two. And you
• 02:04can also image VMAT two
• 02:06by using this ligand DTBS.
• 02:09And you can see on
• 02:10the top panels are healthy,
• 02:12healthy imaging, and then the
• 02:14bottom is PD. And you
• 02:15can see that the disease
• 02:16starts
• 02:17asymmetrically
• 02:18in the in patients,
• 02:20typically on one side. And
• 02:21you can see that there's
• 02:22a loss of both
• 02:24f dopa and d, DTBS,
• 02:27staining.
• 02:27And the other,
• 02:29other way to monitor this
• 02:30sort of both the dysfunction
• 02:32and the loss of, termini
• 02:35early in disease
• 02:36is using,
• 02:37DAT imaging.
• 02:38That is the dopamine transporter,
• 02:40which is used to reuptake
• 02:42dopamine as a clearance mechanism,
• 02:45and, allow for cycling.
• 02:48And so, traditionally, there have
• 02:49been there have been many
• 02:50modalities for imaging this, and,
• 02:53to date now, the DAT
• 02:54scan, which is this,
• 02:56iodine one twenty three,
• 02:58iron,
• 03:01ligand is traditionally used now
• 03:03to identify,
• 03:05new patients
• 03:06for, for with which have
• 03:08a Parkinson's.
• 03:10So there's a now new
• 03:12brand new imaging modality, actually,
• 03:14which is pioneered here, which
• 03:16is called UCBJ.
• 03:18And this is a study
• 03:19by David Matuski's lab in
• 03:21psychiatry.
• 03:23And this is a ligand
• 03:24that actually just looks which
• 03:26binds the synaptic vesicle. So
• 03:28this is not specific only
• 03:30for dopamine, but just all,
• 03:32all synaptic vesicles,
• 03:34and it binds s v
• 03:35two. And even in using
• 03:36a generic,
• 03:38synaptic vesicle marker, you can
• 03:40see that in the
• 03:42in Parkinson's
• 03:43patients, there's less signal, and
• 03:45this is sort of s
• 03:46v two density actually correlates
• 03:49very nicely with movement,
• 03:52severity in these patients.
• 03:55So so the question really
• 03:56is and that what one
• 03:57of the questions that animates
• 03:59us is to figure out
• 04:01why are synapses being dysfunctional
• 04:03and lost in the disease.
• 04:05And this holds the promise
• 04:07of actually
• 04:08disease modifying therapies because this
• 04:11is occurring in the prodromal
• 04:13phase of the disease
• 04:14even before the onset of
• 04:16movement,
• 04:18you know, deficits.
• 04:19And therefore, if we can
• 04:21understand these mechanisms,
• 04:23it holds the promise of
• 04:24sort of disease modifying,
• 04:26therapy.
• 04:27So we are getting clues
• 04:29to understand this from the
• 04:31genetics. So as,
• 04:33was alluded to earlier,
• 04:35Pietro and I study familial
• 04:37genes and really big risk
• 04:39genes because we can model
• 04:40them readily in the lab.
• 04:42And so
• 04:44it includes that that indeed,
• 04:46why why are synapses dysfunctioning
• 04:48from the genetics? So as
• 04:50this was shown earlier on
• 04:52here is the FX size.
• 04:53So on the very top
• 04:55quartered are familial genes. There
• 04:57are twenty four familial genes.
• 04:59And then there are two
• 05:00medium to high risk allele,
• 05:02GBLERB
• 05:03two, which you've already heard
• 05:04about, and then all the
• 05:06many genes that,
• 05:08that are risk alleles that
• 05:09are shown in this,
• 05:11bottom cluster.
• 05:12So in here, listed the
• 05:14genes and the gene name
• 05:16and the proteins, the encode
• 05:17that are actually
• 05:19functioning at the presynaptic.
• 05:21So I should add that
• 05:22in Parkinson's,
• 05:24the vast majority of,
• 05:26effects
• 05:27of the synapse are occurring
• 05:29on the presynaptic
• 05:30side and actually not surprisingly
• 05:32on the postsynaptic side. So
• 05:34the genes that are shown
• 05:35here, you've already heard of
• 05:37alpha synuclein,
• 05:39oxalin, which you heard of
• 05:40in the form of a
• 05:41circular RNA, synaptogenin,
• 05:43which, Pietro works on. And
• 05:45so some of these obviously,
• 05:47like Lerp two also work
• 05:48on the lysosome, but also
• 05:50have impacts on synaptic function,
• 05:52but the ones in red
• 05:53are exclusively presynaptic.
• 05:55So today, I wanna sort
• 05:57of tell you,
• 05:58sort of three vignettes
• 06:00using these genes and trying
• 06:01to understand how these,
• 06:03genes impact actually synaptic function
• 06:06and sort of relate to
• 06:07you there's a convergence of
• 06:09pathways among these various genes
• 06:11that actually impact, synaptic terms.
• 06:13I'm gonna tell you about
• 06:15alpha synuclein,
• 06:16which is and then DNA
• 06:18j six, which encodes oxalate,
• 06:20and then GBA, which is
• 06:22not a presynaptic gene, exactly,
• 06:24as you've heard, a lysosomal,
• 06:26protein, but actually surprisingly impacts
• 06:28synaptic function.
• 06:31Okay. So let's before I
• 06:32make this case, I wanna
• 06:33make the case that synapses
• 06:35in general are highly vulnerable
• 06:37to synapse loss partly because
• 06:40they're executing
• 06:41the synaptic vesicle cycle, which
• 06:44in a tonically firing synapse
• 06:46like the dopaminergic
• 06:47synapse is occurring many times
• 06:49a second.
• 06:50And so the vesicles have
• 06:52to be filled with neurotransmitter
• 06:53fused
• 06:54and then be retrieved by
• 06:56synaptic vesicle endocytosis.
• 06:58So they have they have
• 06:59a very specialized component of
• 07:01proteins, such as synaptic vesicle
• 07:03proteins.
• 07:04And because of the synaptic
• 07:05vesicle cycle,
• 07:07they occur
• 07:08they undergo high rates of
• 07:09conformational changes, and these changes
• 07:11need to be precise in
• 07:13order to allow for fusion
• 07:14at,
• 07:16sort of being linked to
• 07:17the action potential.
• 07:19And as,
• 07:20as as sort of exemplified
• 07:22by the nigra
• 07:24stridal synapse, that the cell
• 07:26body and the synapse can
• 07:27be very far away. So
• 07:29here, the synapse is, the
• 07:31cell body is in the
• 07:32Niagara, but the synapse is
• 07:34at the striatum.
• 07:36And axonal transport actually is
• 07:38pretty slow. Even fast axonal
• 07:41transport is slow to maintain
• 07:42this quality
• 07:44of,
• 07:45quality in this terminal is
• 07:47difficult because of that. You're
• 07:48not getting new protein constantly.
• 07:50And there's while there is,
• 07:52protein translation mostly on the
• 07:54postsynaptic
• 07:55side, its role in the
• 07:57presynaptic side is much more
• 07:59limited.
• 08:00And, obviously, there are presence
• 08:02of aggregation prone proteins.
• 08:04And so this is best
• 08:06obviously exemplified
• 08:08by alpha synuclein.
• 08:09So you saw this right
• 08:11hand side of the graph,
• 08:14earlier. So but on the
• 08:15left hand side is just
• 08:17disease risk versus expression. And
• 08:19you can see that
• 08:21the the
• 08:22the duplication and the triplication
• 08:24which increase expression
• 08:26linearly increase disease risk, while
• 08:29the mutations
• 08:30actually increase aggregation.
• 08:32So they all increase aggregation.
• 08:34And the question is, but
• 08:35does aggregation occur at the
• 08:37synapse?
• 08:38So we previously and we
• 08:40and others have shown that
• 08:41synuclein,
• 08:44since its discovery when it
• 08:45as a torpedo vesicle protein
• 08:47is a synaptic vesicle protein,
• 08:49so it binds powerfully to
• 08:50synaptic vesicles.
• 08:52And this is shown by
• 08:53immunogold, which are these little
• 08:55black dots,
• 08:56and that synuclein is at
• 08:58rest is always found on
• 08:59synaptic vesicles. And this is
• 09:00quantified here at the bottom.
• 09:02So sixty percent of them
• 09:03are on the vesicle
• 09:05with around third, twenty five
• 09:07percent on plasma membrane.
• 09:09But, surprisingly, what we discussed,
• 09:11if you stimulate,
• 09:13nerve terminals, what happens is
• 09:14the synuclein comes off, and
• 09:16then it's it's found mainly
• 09:18on the membrane. And then
• 09:19when you repolarize the terminal,
• 09:21then the vessel it goes
• 09:23back onto the vesicle. So
• 09:24it's synuclein,
• 09:26localization
• 09:27within the terminal is dynamic
• 09:29and and linked to synaptic
• 09:30activity.
• 09:31So our control is synapto
• 09:33brevin, which is an integral
• 09:34vesicle protein, and you can
• 09:36see it's mainly on the
• 09:37vessel.
• 09:39So why why does this
• 09:40matter? So this matters because
• 09:42there's some very nice work
• 09:44from Ulf Detmer's lab at
• 09:46Harvard at Brigham,
• 09:48showed that that this that
• 09:50synuclein is actually being phosphorylated
• 09:52as a function of the
• 09:53synaptic vesicle. So they showed
• 09:55that that as the vesicle
• 09:57cycles, that synuclein is being
• 10:00phosphorylated
• 10:00as serine one twenty nine.
• 10:03Historically, we actually thought this
• 10:05phosphorylation
• 10:06was purely pathological,
• 10:08but now it's appreciated that
• 10:10this is occurring as part
• 10:11of the normal physiology of
• 10:13the protein. Every time the
• 10:14protein comes off the vessel,
• 10:16it's getting phosphorylated
• 10:17up for polo
• 10:19polo like kinase two, and
• 10:20then the phosphorylation can be
• 10:22removed. And this was what
• 10:24is resulting in actually
• 10:26the aggregation
• 10:27of the protein
• 10:28in the terminal. So there's
• 10:30been long standing data in
• 10:31the field that actually why
• 10:33you can see Lewy bodies,
• 10:35which are these sort of
• 10:36bright objects in, in in
• 10:38pathology.
• 10:39There's a lot larger and
• 10:41vast more amount of sort
• 10:43of smaller oligomeric
• 10:45species that are found in
• 10:47presynaptic terminal, and this is
• 10:49sort of explaining that the
• 10:50phosphorylation
• 10:51event that precipitates
• 10:53this is actually occurring at
• 10:55the terminal.
• 10:56So the question is what
• 10:57what are the consequences
• 10:58to the synaptic function,
• 11:01for this aggregation?
• 11:03So we we show this
• 11:04when I first started my
• 11:05lab here, Dale, that if
• 11:07you overexpress and you aggregate
• 11:08synuclein internals, you actually get
• 11:11profound effects on neurotransmission.
• 11:13So here in blue, which
• 11:14is hidden is the wild
• 11:15type. And then if you
• 11:17overexpress
• 11:18if you delete all synucleins,
• 11:20actually, synaptic transmission gets better.
• 11:22But if you overexpress
• 11:24human,
• 11:25alpha synuclein and cause aggregation
• 11:27in the tunnel, neurotransmission
• 11:29goes down. And this is
• 11:30actually specific for the human
• 11:32subtype, which can aggregate
• 11:34unlike the mouse, which doesn't
• 11:36readily aggregate in the system.
• 11:38It's just like wild type.
• 11:40So this this data has
• 11:41been replicated by many labs.
• 11:44And so that the bottom
• 11:45line is that you overexpress
• 11:47and aggregate synuclein
• 11:48in the nerve zone, you
• 11:49get neuro decrease in neurotransmission.
• 11:52So this is shown by
• 11:53Stephanie Craig's dad at the
• 11:55nigrostriatal
• 11:56synapse.
• 11:57And you can see that
• 11:58overexpression of synuclein and thus
• 12:00for it will dampen trans
• 12:03oh,
• 12:04so what what are the
• 12:06why is neurotransmission
• 12:07input output curves actually decreasing?
• 12:10So one of the ways
• 12:11it's doing this is because
• 12:12of structural reorganization of the
• 12:14synapse, which I'm not gonna
• 12:15talk about today, But the
• 12:17other is because it dampens,
• 12:19and retrieval of the membrane
• 12:21and synaptic vesicle endocytosis
• 12:23and nerve terminals as shown
• 12:25by florin imaging, which is,
• 12:27a pH sensitive GFP that's
• 12:30monitoring vesicle trafficking.
• 12:32And as the curves get
• 12:33as the tau as the
• 12:35vesicle
• 12:36retrieval is happening, it
• 12:38the GFP is sort of
• 12:39quenched. And therefore,
• 12:41if this is slower, this
• 12:42means that endocytosis
• 12:44is slower, and you can
• 12:45calculate this as a decay
• 12:47constant of tau.
• 12:49So this is what synuclein
• 12:51is doing at the terminal.
• 12:52It also has profound struct
• 12:54structural changes to the pool
• 12:57vesicle pool dynamics, which which
• 12:59are already published, and many
• 13:00groups can show this.
• 13:02So okay. So that's that's
• 13:04one vignette. So the second
• 13:06vignette I wanna talk about
• 13:07is auxilin, which is DNA
• 13:09j c six, which is
• 13:10of great interest to you.
• 13:12So
• 13:14so this was a gene
• 13:16identified in families which have
• 13:18early onset Parkinson's.
• 13:20And what we what it
• 13:21has one known function. It's
• 13:23a chaperone.
• 13:24It basically
• 13:26uncoats this clathrin coated vesicles
• 13:28that are formed as as
• 13:30a part of synaptic vesicle
• 13:31endocytosis
• 13:32to generate a nascent vesicle
• 13:35allowing it to be actually
• 13:36refilled with neurotransmitter.
• 13:39So,
• 13:40what happens is that,
• 13:42it's already Pietro and Loyce
• 13:44Green's lab previously showed that
• 13:46if you in in mice
• 13:48that lack oxalyn,
• 13:49endocytosis
• 13:50is not surprisingly slow using
• 13:52the same fluoren assay, which
• 13:54is this pH sensitive hooked
• 13:55to a synaptic vesicle protein.
• 13:58And so the question what
• 13:59we tested is whether this
• 14:01oxalyn
• 14:02mice are actually a good
• 14:04model for Parkinson.
• 14:06So we did longitudinal
• 14:08behavioral analysis on large cohorts
• 14:10of mice, and we could
• 14:11show that in a wild
• 14:13type mouse, which you saw,
• 14:14it would scurry back across
• 14:15this balance beam. But the
• 14:17oxalate mice is still sort
• 14:18of getting across this beam.
• 14:20And so you can see
• 14:22that as a wild type
• 14:24as a function of age
• 14:25can do this assay even
• 14:27up to fifteen months, but
• 14:29the knockout is actually showing
• 14:31an age dependent
• 14:32decrement in motor function.
• 14:34And most importantly,
• 14:35this can be rescued by
• 14:37giving l dopa, which is
• 14:39the standard treatment for Parkinson
• 14:41patient. So you can see
• 14:42individual traces of mice that
• 14:44are nine to twelve months
• 14:45old that they can improve
• 14:47in their motor performance when
• 14:49they do this. And this
• 14:50is the cumulative data.
• 14:53We also tested and showed
• 14:55that in these mice, there's
• 14:56age dependent loss of dopaminergic
• 14:58neurons in the nigra, and
• 15:00this is quantified
• 15:02by sterology. So you can
• 15:03see there are forty percent
• 15:05loss of neurons as a
• 15:06function of age.
• 15:07And and the third feature
• 15:09of Parkinson's that everybody looks
• 15:11for is to see whether
• 15:12they have synuclein pathology,
• 15:14and we could show that
• 15:15in an age dependent manner
• 15:17in the nigra, which is
• 15:18labeled with t h, that
• 15:20there is increased phosphorous,
• 15:22serine one twenty nine phosphorylation.
• 15:25This phosphorylation is not restricted
• 15:27to t h positive cells,
• 15:29but,
• 15:30but is found throughout the
• 15:31brain. And it's not like
• 15:33the somatic aggregation of Lewy
• 15:35bodies, but much more presynaptic
• 15:37like aggregates that we see,
• 15:40in in the in the
• 15:41previous pictures that I showed
• 15:42you. And this is the
• 15:43quantification here shown on the,
• 15:45shown on the right.
• 15:48Okay. So because this data
• 15:50is published, I'm just gonna
• 15:51summarize what we see mechanistically
• 15:53in the oxalate mice. When
• 15:56so I already told you
• 15:57that they have this deficit
• 15:59in clathrin uncoating.
• 16:00And as a result, what
• 16:01happens is clathrin coated vesicles
• 16:04accumulate.
• 16:05The other thing that happens
• 16:06is that the synapse to
• 16:08generate these vesicles uses other
• 16:10modes of endocytosis,
• 16:12which don't have the same
• 16:13quality control.
• 16:15And as a result, if
• 16:16you look at proteomics of
• 16:18the vesicles that are in
• 16:19the knockout,
• 16:20their their composition is totally
• 16:22different. And we think that
• 16:23because of that, they don't
• 16:25have key proteins like vesicle
• 16:26amine transporter,
• 16:28and dopamine will accrue not
• 16:31within the vesicle, but in
• 16:32the cytosolic milieu of the
• 16:34presynaptic terminal.
• 16:35And dopamine is already known
• 16:37that if it it is
• 16:38very oxidative
• 16:40prone and that it forms
• 16:41these intermediates like called DOPAL
• 16:44and DOPAC.
• 16:45And DOPAL is very increased
• 16:47in these oxalate knockout mice,
• 16:49suggesting that dopamine forms adducts
• 16:52with a whole bunch of
• 16:53proteins in the terminal and
• 16:54causes toxicity.
• 16:56And what we also can
• 16:58show is that both synaptic
• 17:00vesicles and clathrin motor vesicles
• 17:02are being cleared by autophagy
• 17:04in the presynaptic
• 17:05terminal.
• 17:06And the last thing that
• 17:07we see is that DAT,
• 17:09which is the dopamine transporter,
• 17:10which is being used in
• 17:11the in the clinic,
• 17:13is trapped in these sort
• 17:14of large worlds. And some
• 17:15really beautiful imaging,
• 17:17EM data from Pedro's lab
• 17:19also showed this in their
• 17:20synaptogen
• 17:21in mice.
• 17:22And I show you a
• 17:23picture from our mice, the
• 17:24oxalate mice. You can see
• 17:26these large membrane worlds in
• 17:27which that is,
• 17:29is sequestered. And we think
• 17:31that this may be a
• 17:32common modality
• 17:34through which
• 17:35many Parkinsonian
• 17:36models are impacted,
• 17:38that that trafficking
• 17:39is controlled by endocytic
• 17:41pathways and that this is
• 17:43impacted
• 17:44across many PD,
• 17:46genetic forms of PD and
• 17:48maybe even sporadic forms of
• 17:49PD. Okay.
• 17:53So that's that's a little
• 17:55vignette about,
• 17:57oxalate. And the last vignette
• 17:58I wanna tell you is
• 17:58about GBA. And as you
• 17:58already
• 17:58heard, wanna tell you
• 18:00is about GBA. And as
• 18:02you already heard from Steve's,
• 18:04talk and, also alluded by
• 18:06Clement's talk, that GBA
• 18:09is one of the biggest
• 18:11risk factors with Lerp two
• 18:13for
• 18:14Parkinson's disease. Around five percent
• 18:16of all PD patients have
• 18:18GBA mutations.
• 18:20And so we're we have
• 18:21been had a long standing
• 18:22interest in this gene.
• 18:24GBA encodes this lysosomal enzyme,
• 18:27so it's not found in
• 18:28the presidaptic terminal.
• 18:30It's it's basically
• 18:32it's a glucosidase
• 18:33that's removing,
• 18:35ceramide,
• 18:36glucose
• 18:37from glucose and ceramide.
• 18:39So we we had previously
• 18:41generated long lived mice,
• 18:43that are very accurate models
• 18:46for GBA linked Parkinson,
• 18:48and we have also crossed
• 18:49these mice to synuclein transgenic
• 18:52so so you can get,
• 18:53wild type and GBA l
• 18:55triple four p mutation on
• 18:57a null background,
• 18:59on a wild type background
• 19:01and a and a synuclein,
• 19:03transgenic
• 19:04or a sensitized background.
• 19:06And we have done so,
• 19:07again, longitudinal
• 19:09analysis of these mice, but
• 19:10I'm not gonna show this
• 19:11to you, but to say
• 19:12that
• 19:13these mice have profound cognitive
• 19:15deficits on their own very
• 19:17early in life. So even
• 19:19at three months of age,
• 19:20GBM mice cannot do,
• 19:22many cognitive tasks, including fear
• 19:25condition and novel object recognition.
• 19:27But what is very surprising
• 19:29is that they have these
• 19:30profound deficits
• 19:32even though they have no
• 19:33alpha synuclein
• 19:35pathology in these mice. And
• 19:36this is the quantification,
• 19:38three months,
• 19:39YOSAP and GBA.
• 19:41But interestingly, if you have
• 19:43a GBA mutation on a
• 19:44synuclein background,
• 19:46it greatly
• 19:47accelerates the pathology of the
• 19:49synuclein.
• 19:50And this is sort of
• 19:51increases with age. We've aged
• 19:53these mice out to now
• 19:54eighteen months, and they don't
• 19:55seem to have any, synuclein
• 19:58pathology.
• 19:59So we've done a single
• 20:00cell RNA sequencing trying to
• 20:02understand the basis for this
• 20:03cognitive phenotypes,
• 20:06and what we have done
• 20:08sort of a pathway analysis.
• 20:10And what's surprising for us
• 20:12is in neurons, the biggest
• 20:14pathways
• 20:15are all related to synaptic
• 20:17vesicle endocytosis.
• 20:18We actually do not see
• 20:20transcriptual changes associated with lysosomal
• 20:22proteins, but actually only,
• 20:25synaptic pathways in neuron.
• 20:29So I sort of sort
• 20:30of summarize, yeah, summarize all
• 20:32these three pieces of the
• 20:32thing is that the synaptic
• 20:34vesicle endocytosis
• 20:35is a major pathway in
• 20:37endo in Parkinson's
• 20:39disease.
• 20:40And, you know, we recently
• 20:41did a single cell and
• 20:43multiomic
• 20:44transcriptomic
• 20:45analysis of
• 20:46sporadic Parkinson patient brains,
• 20:49in collaboration with David and
• 20:51Le. And we could see
• 20:53that some of the proteins
• 20:54that genes that are actually,
• 20:57familial genes, they also show
• 20:58similar patterns in the sporadic.
• 21:00For instance, synuclein is expressed
• 21:02increased and for instance,
• 21:06oxalate is decreased. So we
• 21:08think that even though we're
• 21:09studying familial
• 21:11disease, that this has a
• 21:13bearing on sporadic disease.
• 21:15So with that, I would
• 21:16like to sort of
• 21:20thank the people who made
• 21:21the work. So the the
• 21:23project was actually spearheaded by
• 21:25Corina Vargas. She has her
• 21:26own lab in University of
• 21:27Pittsburgh,
• 21:28and then the GBA and
• 21:30work was spearheaded by Vidya
• 21:32Dara who just started his
• 21:33own lab in Roseland Franklin.
• 21:35All the people in red
• 21:36are team Synuclein,
• 21:38team GBA,
• 21:40and the rest of my
• 21:41labs and and collaborators. Thank
• 21:43you.