The Research Behind Hope: Decoding Parkinson’s with Nikhil Panicker

In this episode, we explore what really happens to our brains when Parkinson's takes hold.

We go deep into the brain, inside these cells, at a microscopic level, and try to understand this.

We explore the tools and the techniques that scientists use to study this disease, and how are new treatments designed?

I'm joined here by my friend and colleague, Dr. Nikhil Panicker, a neuroscientist and an assistant professor at the Cleveland Clinic. His lab is dedicated to understanding Parkinson's disease and dementia with Lewy body. The goal of his lab is to understand the mechanisms behind these diseases And finding ways to slow or stop the disease. I hope you enjoyed this conversation and find it as eye-opening as I did.

Transcript

Introduction to episode

Akshata 0:00

Hello and welcome back. In this episode, we explore what really happens to our brains when Parkinson's takes hold. We go deep into the brain inside the cells at a microscopic level and try to understand this. We explore the tools and the techniques that scientists use to study this disease and how are new treatments designed. I am joined here by my friend and colleague, Dr. Nikhil Panicker, a neuroscientist and an assistant professor at the Cleveland Clinic. His lab is dedicated to understanding Parkinson's disease and dementia with Louis Body. And the goal of his lab is to understand the mechanisms behind these diseases and find ways to slow or stop the disease. I hope you enjoy this conversation and find it as eye-opening as I did. Hi, I'm Dr. Akshata Almad, a neuroscientist, and this is Journey of a Withering Brain, bringing hope through science and human connection. Welcome to the show. I'm so excited to have you on my podcast, and this series focused on Parkinson's disease. And I'm looking forward to learn and sharing your work with our audience.

Nikhil 1:38

Thanks so much for having me. I'm excited to be here.

Akshata 1:42

So I would like to first start off by understanding like what initially drew you to Parkinson's disease research and you know how it's evolved over time for you.

Nikhil 1:54

Sure. It's a great question. So Parkinson's is a degenerative brain disorder that is essentially uncured as of now. So while there are diseases that can uh while there are drugs that can affect um that can help with symptoms, uh Levadopa, in fact, has been around since the 60s. Um PD, which is characterized by uh neuron loss in the mental mid pain, proceeds unabated in the presence or absence of Levadopa. So it's it's it's that that that frontier, the fact that uh neurodegeneration um has not been curbed in in any disease model uh in any patient yet. That's what I guess drew me to study Parkinson's a bit more uh and and and learn more about the disease.

Akshata 2:40

Yeah, and I guess you're referring to the I guess the disease modifying therapies, which have not yet really been successful in Parkinson's disease. And I'm curious, like how has your lab been, you know, what is the research focus and how it's been contributing to maybe understanding some of these mechanisms?

Nikhil 2:59

Right. So uh as you said, there is no disease modifying therapy for Parkinson's. Uh, and my lab um is focused on, well, right now we're focused on non-neuronal cells in the ventral midbrain in Parkinson's, uh, immune cells like microglia, and how brain inflammation fits into the whole process of neurodegeneration. So uh a lot of my work um studies these long-lived immune cells in the brain and how they can actually act to amplify or sometimes curb disease progression, and how they can be actually manipulated to um to either speed up or slow down disease, and then we use tools in my lab to sort of uh to sort of control these pathways in vivo and in in in stem cell models.

Akshata 3:48

So,

Introduction to Parkinson's

Akshata 3:49

a little background information for our listeners here. The part of the brain that's affected in Parkinson's is an area called the midbrain, and the neurons in this region are called the dopaminergic neurons. These are the neurons that make dopamine, the neurotransmitter. And when these cells start to die, it affects movement. So that's why the doctors give L-dopa to the patients. That way, instead of making dopamine, you just directly take it to compensate for the lost neurons. There are also cells that are not neurons in the body, and that's what Dr. Panicker is talking about. A lot of the therapies are about resolving symptoms by taking L-dopa. What scientists are trying to do is develop disease modifying therapies, which just doesn't treat the symptoms but actually tries to fix the real problem or slow the disease or halt the disease. And those are called as disease modifying therapies. That actually brings me to my next question. Like, if you don't mind sharing with our listeners, how do researchers and scientists like yourself study Parkinson's in the lab?

Nikhil 5:09

You mean like what sort of models we use?

Akshata 5:11

Yeah, yeah. Like, how do you go about studies this very complex disease?

Nikhil 5:16

Right.

Modeling Parkinson's

Nikhil 5:17

So we could we could devote uh a whole hour to to to to that topic alone. Um I guess I guess uh modeling Parkinson's began back off back in the 60s with uh the six OHDA mouse model, which is six hydroxydopamine, um, which is a quick neurotoxin. So it's a it's a modified version of dopamine, which is a neurotransmitter. Um and if you inject it unilaterally into um uh into a rodent brain, it quickly mediates neuron death. Um and you know, Parkinson's is characterized by dopamine neuron loss. So for the longest time or for a long period of time, that was the gold standard. Um then oh, so uh by the way, I've I I think I've been in the game long enough to have worked with pretty much every model of Parkinson's, which sort of belies how how how how old I am, but it's I've been in the field for a while. So I have worked with the 6OHDA mouse model as well. Um and then things moved on to the MPTP model. Um, so MPTP um is a derivative of um MPP, which is uh uh a meth analog, and uh how it actually happened that uh a bunch of addicts um injected themselves with what they thought was the math analog and woke up the next day essentially with Parkinson's disease. Um and then they became a famous cohort of patients uh that were known as the Langston's addicts. Um and then eventually the compound that they injected themselves with um elicited Louis body formation and and essentially was used or sort of co-opted to uh to become a non-human primary model of Parkinson's. And eventually that was moved to mouse models. Um and the MPTP mouse model came along and now has thousands of papers uh devoted to it. And finally things moved on uh when synuclein became uh was first discovered. Uh, and then we we we developed transgenic and non-transgenic models of alpha synuclein, which is a protein that forms clumps in Parkinson's disease. Um, and a lot of current work sort of delves around exploring how these clumps can propagate from one brain region to the next, and how uh brain toxicity and pathology can sort of move or be transmitted. So I we use a lot of synuclein models these days. Um and finally, we use a lot of sort of stem cell-based models. So we used iPSCs to differentiate them into dopamine neurons, into microglia, and use co-culture or separate culture to sort of uh elicit how these cells talk with each other and um function together to uh to mediate neuron death.

Akshata 8:04

In summary, scientists use animal models such as rat and mice to study Parkinson's. They also use human cells, and these cells can be from someone with Parkinson's, so you can take stem cells, which can be converted into any cell in this body. It could be a brain cell like a neuron, and comparing a brain cell from someone with Parkinson's and those that don't have Parkinson's can allow the researcher to understand what really happens inside the brain when someone is affected with Parkinson. There are a number of genes that are implicated in Parkinson's, and one such gene is called as the alpha-synuclein gene or the SCNA gene. This gene makes the protein called synuclein, which when starts clumping inside the brain cells called neurons can be toxic and causes these neurons to die. So they can also use animal models that have these genes that are faulty. So now the researchers can use both animal models as well as human models to understand what happens in this disease. In this next section, we are gonna dive

Genetics of Parkinson's

Akshata 9:30

more into the genetics of Parkinson's. Yeah, and and you actually bring it to a really interesting thing about the whole game changer of genetics that's happened in Parkinson's. And I'm just wondering, like, you know, if if you could share some of the relevant genes, there's there seem to be like an explosion of different genetic factors, and and how that's you know changed the field in general of Parkinson's and and what are some of the big mutations that people are focused on?

Nikhil 10:03

Right. So that's a that's a fantastic question. Uh, if you look at popular magazines or even um scientific journals before the year 1998, Parkinson was almost universally considered to be a non-genetic disease. It had no genetic component to it. And the way people made those conclusions is there was there were there were twins. So there'd be one among the pair who got Parkinson's and another one who didn't. And of course, twins shared the same genome. So they made the conclusion that Parkinson's is not genetic. Then, of course, things changed in 1998 when the first inherited form of Parkinson's was discovered, uh, which is autosomal dominant, and that was the SNCA gene that encodes synuclein. Um, and in the same year, again, clumps of synuclein were found in Lewy bodies, the kinds that are found in most PD patient brains. So that really changed the game quite a bit. Uh, and synuclein itself is uh it's it's also called PARK1 . It's the first Parkinson's associated gene. It's also PARK3 because triplicates of synuclein uh triplications in the SNCA gene also cause inherited Parkinson's. Uh and I think now we're up to PARK19, uh, if not more. So there's um um several genes that now cause monogenetic inherited forms of Parkinson's. Um, the Parkin and Pink One genes are pretty big examples of that, as is LRKK2. Um and I think GBA has really taken off as uh as a PD-associated gene that may not be highly penetrant, but it's it's extremely common. And it's perhaps uh I guess GBA and LRKK2 are um, I guess not as penetrant, but extremely common uh disease mutations that can predispose you to getting Parkinson's. So in a nutshell, why it was thought to be completely non-genetic before, uh now genetics plays a pretty important role in, of course, inherited forms, but even in non-inherited forms, like that you you will find mutations um that contribute to the the PD onset.

Akshata 12:10

And you also study Lewy body dementia. So I'm just curious, like, do these genetic predispositions can they help distinguish whether it's going to be purely Parkinson's or it's gonna be like somewhere in that spectrum of Parkinsonianism?

Nikhil 12:26

That's a great question. Um, I think a Lewy body dementia diagnosis is really hard. Um, and I'm not sure if genetics will make it easier or or harder. Uh essentially, people who are diagnosed with Parkinson's, pure Parkinson's, tend to uh tend to have motor symptoms, of course, which may progress to dementia over a period of time. And folks with Lewy Body dementia have uh concomitant motor dysfunction, so they have a loss of dopamine neurons, but they also have fluctuating concrete dysfunction, and it's fluctuating, so it isn't typical like like like uh the Alzheimer's disease, uh, and they're more prone to hallucination. So, in other words, uh distinguishing DLB from Parkinson's is is fairly complicated, it's it's really hard. And I don't know if genetics makes it harder or or easier, really, because um many of the genes associated with pure Parkinson's, SNCA Parkinson for instance, are also associated with uh with DLB.

What happens in a cell with Parkinson's?

Akshata 13:30

And I guess at a cellular level, um what like what really happens? Like there is aggregation and and there, I guess there's different mechanisms, and there's this thought to be lack of I guess clearance of these pathological proteins. And like, could you speak a little bit to that? Like, what are potential cell-based mechanisms that are known?

Nikhil 13:53

Um, so again, that's a fantastic question. I think there's a there's a plethora of things going wrong in a cell that's accumulating misfolded synuclein. Um, one, if you look at a Lewy body, it it looks abnormal. It's it's it's a it's a micron, two microns big inside uh a neuron. So almost certainly that's gonna negatively affect cellular functions. Um second, misfolded synuclein is toxic, um, and it does um cause or elicit cell death pathways. Not apoptosis, surprisingly, but a whole host of other um somewhat exotic cell death pathways. Uh a third, somewhat underdeveloped um um um I think area of of investigation is that synuclein actually has endogenous means it's it's it's a fairly abundant uh protein in a neuron. So it has endogenous functions um associated with the the transmission of uh of synapses, synapse organization. So when synuclein oligomers form, those functions are obviously also depleted. So I think you have the concomitant depletion of endogenous synuclein function um and a gain of its toxic function um that can act in in concert to um remediate neuron dysfunction and death.

Lysosome- vacuum cleaner of the cell!

Akshata 15:19

In summary, we talk about how proteins such as the nuclei can lead to Parkinson's disease and how and what happens to that protein in a cell. So all proteins in our body have a certain shape, and that shape allows them to function well. When that shape changes or becomes misfolded, that protein cannot function anymore. In fact, that protein can also become toxic to the cell in that case. And sometimes these proteins can form clumps and accumulate and build up inside the cell. Think of it as a disorganized house in which there is a lot of garbage, and as that garbage continues to accumulate, it can affect one's health. So, what we need is a cleaner, you need a vacuum cleaner. In this next section, we are going to talk about one such part inside the cell called as a lysosome, which is in essence a vacuum cleaner that can get rid of these proteins that are accumulating and being toxic. And I guess some of these, like in what you just mentioned about compromise of the machinery, some of the discovered mutations seem to be linked with lysosomal dysfunction, which uh, if you don't mind sharing, like you know, what what a lysosome, like you know, what it essentially does and how they might those mutations might potentially be contributing to increased accumulation or I guess lack of clearance of these protein aggregates.

Nikhil 16:57

Right. So um I guess the lysosome and mitochondria are uh two organelles that are have been pretty intimately associated with Parkinson's. Uh, and as you said, um lysosomes generally sort of either tag or are uh required for the disposal of um dysfunctional organelles, proteins. So if there's any um cellular machinery that that that compromises lysosomal function, you'll have the natural buildup of um of potentially toxic aggregates. Um so that's been fairly common in the space of uh of Parkinson's, uh, as is uh as is mitochondrial dysfunction, um, which is actually something that that that we've recently gotten into quite a bit.

Akshata 17:44

Um

Mitochondria- energy producer of the cell

Akshata 17:45

and uh a lot of our work deals with how um compromised sorry if you could just introduce what mitochondria is for our audience.

Nikhil 17:54

Okay, uh I'm gonna try really hard not to use the word powerhouse of the cell. Um but I mean that's that's what we all learned, right? So um um of course mitochondria are energy producing organelles in the cell. Um and um um well let me let me tell you like a a bit about what we've been investigating, just because I'm sort of a little biased.

Akshata 18:21

Absolutely, please.

Nikhil 18:22

Yeah, yeah. So um mitochondria obviously get a great trap, like energy-producing organelles, and and they can actually be shuttled or shared between cell types, which is a fairly uh sort of underexplored phenomenon. It's called horizontal mitochondrial transfer. Um, and you would think that you know transferring mitochondria from any cell to any recipient cell would bode particularly well for the recipient cell. I mean, why wouldn't it? It's getting a source of um actively respiring mitochondria that are providing it with uh a source of energy. And that has been almost almost invariably the case. So uh, for instance, in the settings of uh of Parkinson's um immune cells called microglia can donate mitochondria to healthy mitochondria to other neurons or to other microglia. And this uh respectively, it's it's sort of uh prevents cell death and prevents inflammation uh when it's when it goes into uh microglial cell. Now, on the flip side, um Parkinson's is characterized by mitochondrial dysfunction. So not only are dysfunctional mitochondria not helpful, uh they're actually directly engage cell death pathways. In immune cells, they actually act as triggers for innate immune strengthening uh complexes. So having non-functional mitochondria in any cell type is uh it does not bode well for the organism.

Akshata 19:52

So, as Dr. Panicker shares, that besides lysosomes, mitochondria is another part of the cell that's important as this particular organelle makes energy for the cells. And it's known that in Parkinson's disease, mitochondria are affected. So when the neurons have bad mitochondria, they don't have energy, and specifically the dopaminergic neurons are affected and they die. His lab studies this exciting new direction about the immune cells in the brain called as microglia. These cells

Microglia- protector of the brain

Akshata 20:30

engage in inflammation and they try to help the neurons by giving their own mitochondria. But when the overall brain is affected, it causes the cells, the mitochondria from the microglia to also be bad. We will dive a little bit further about the role of microglia, which are critical for all neurological diseases. These cells, microglia are just really popping up everywhere in the whole neuroinflammation field, and that's kind of uh what your lab studies and and is it all bad, like what it does, and and you know, like what I guess how do you see it in from a therapeutic perspective? Like, are all microglia bad? Like, you know, are you trying to tease that out or saying like we should just get rid of microglia? Like, just just curious, like in terms of Parkinson's or you know, any neurological diseases as such?

Nikhil 21:31

Um, it's a great question. I I know uh we can't get rid of all uh we can't get rid of all microglia. Although if you do it in a mouse, the mouse is perfectly healthy. So you but um um but obviously I think microglia, like all cells, evolved to to serve pretty critical roles in the developing and of course in the adult brain as well. So microglia do represent the only or the primary line of defense when it comes to um, I guess, clearing protein aggregates. So again, aggregates in the brain are professionally cleared by microglial cells. And there's all sorts of protective functions that microglia also serve. So getting rid of them, I guess, completely would would not serve uh well truly protective function, I guess. But that being said, um uh uh like you said the hyperactivation of these these cells by protein aggregates leads to this like uncontrolled inflammation. Um and in those settings, so in say in a PFF mouse model, if you get rid of all microglia, uh well, some studies have shown that it is protective. So you can actually delay the onset of disease cause. Is that really you know transferable to a human patient? No. Um perhaps that's where the sort of scalpel over sledgehammer approach is be most propitious, um, where you can sort of inhibit certain specific pathways in microglial cells that are perhaps most damaging while um still maintaining their protective clearance functions and other protective functions. So that's how I would approach that that that problem.

Akshata 23:16

Um I'm curious, what is your lab focused on in terms of like you mentioned about the I think it's really pretty cool, like understanding the mitochondrial transfer between these cells. Um is that the primary uh research? And I guess what other mechanisms focused on microglia is your lab studying?

Nikhil 23:35

So um right now we have several sort of really interesting ongoing projects. One is on the mitochondrial transfer stuff. Uh, second project that that's that's coming up quite a bit, uh, that's um we're getting really excited about is the induction of uh microglial lipid droplets.

Akshata 23:52

I

Shared ways to target neurological diseases

Akshata 23:53

see that sounds really exciting. And it it it also appears that studying a like these mechanisms is kind of a shared mechanism across some of these diseases. And hopefully understanding them is going to expand not just like you know, one, but like several other uh diseases, uh hopefully developing therapeutics for that.

Nikhil 24:13

Oh, uh I I I I truly hope so. So it's it's been a long-standing goal uh in my career um to sort of identify mechanisms that are shared across different disease types uh and that can be used to hopefully drug not just uh Parkinson's but other disorders that are also characterized by protein aggregation. And some of the stuff we're doing is actually uh working out in that space. So uh I study inflammasomes, which we've spoken about before. Um, and there have been lots of studies that have implicated inflammasomes and other brain disorders as uh as well. And we've expanded our work into the settings of uh ALS and FTD in collaboration with uh Rodrigo Lopez Gonzalez, who I share lab space with. And um, we have a few ongoing projects that sort of delve into these commonalities between apparently disparate disease types, uh, but you know, my dear have been have been implicated in in both disease types. So um that there do seem to be commonalities, and I'm I'm I'm I'm pretty optimistic that um some of these commonalities will work out hopefully and uh and and lead to potential drugs.

Akshata 25:29

That is actually really great to hear for everybody who's and and you know, patients and families, and everyone who's working um hard to find something. And I want to actually come back to one of the things that you mentioned initially about um, I guess the models that are built in Parkinson's. And it appears that a lot of them are these toxic chemicals which are used to generate these models, and and there is now a lot of uh awareness that you know there are pesticides and chemicals that are linked to development of Parkinson's, and and it's not just that there's like other environmental factors called as like I guess exposures called as exposomes. And and I'm just wondering like if you could speak a little bit to that and how um that's been uh you know how how that's been studied in the field in general.

Nikhil 26:19

Yeah, you're again uh absolutely uh on the money. So um it was actually the MPTP studies um that were done back in the 80s, um, that led to the connection between Parkinson's and and pesticides. So MPTP was found to act as a

Exposomes

Nikhil 26:38

mitochondrial toxin. Um, and many pesticides function exactly the same way. Rotenone, for instance, is a is a mitochondria is a is a positive control now for mitochondrial uh inhibition. And shortly after those MPTP studies, I think it was uh studies in Canada that linked exposure to pesticides with the risk of acquiring Parkinson's. Um and of course, that field truly has taken off. And again, um environmentally linked Parkinson's or non-inherited Parkinson's is or constitutes the lion's share of Parkinson's disease cases. So, yes, it's certainly um picking up quite a lot of uh of pace. Um and I think you talked about the the exposome.

Akshata 27:25

Yeah, yeah. Like I guess that's the buzzword now, but also like what's been studied a lot. And I guess I'm curious both from what constitutes exposome and also how I don't know, I guess how we could realistically learn and apply that to to research and you know, like actually potentially I I don't know what we could change, but I did see this crazy article where it's like, oh, anybody who's living a mile within like a golf course, right? Like, is this this high incidence of developing Parkinson's? Because I guess all those nice manicured golf courses have been applied with a lot of pesticides, and it's kind of scary, like when you think about it. So I'm just like wondering what else has been thought of, you know, in terms of exposure and and causing Parkinson's.

Nikhil 28:12

Right. So I think uh the term exposome was was was coined by uh by by by Chris Wilde. Um and I think he um uh in in in the Parkinson space, it was Gary Miller who popularized it. Um and I think their rationale for looking at this is that I think 70% of diseases are non-communicable, and the great majority of these uh are driven by environmental exposures. Um Parkinson's especially is is pretty strongly linked to environmental uh causations, including pesticides. Um and yeah, I mean, not only does um does exposure to pesticides increase the risk of idiopathic or non-inherited Parkinson's, I'm sure that it'll actually, or I'm reasonably certain that it'll also predispose people with um, I guess, non-highly penetrant mutations into also getting PD. So uh there's a pretty strong link, I think, of uh environmental exposure to Parkinson's. And um and I guess we'll have to to defer to uh to to Gary Miller to exposome guru.

Akshata 29:30

Yeah, no, that's that's actually, and and I guess that's kind of been the source of all of these model development as well, and and it's been it's been helpful to kind of just learn about that and and see like you know what else might be from a model development in addition to genetic predisposition. Um, because clearly, as you said, like even though there has been an amazing amount of genetics, you know, and the screen and all of that, that's been helpful just from awareness perspective, there is still a black vast majority who are not necessarily genetically predisposed.

Nikhil 30:05

Right, right, right. And before I forget, uh that there is, of course, uh there are multiple mouse models or other models uh that don't involve synuclein itself and that involves say rotenone or or other toxicants that can also induce neuron death. Um and um I do think that the rotenone model especially is sort of becoming more reproducible as as more labs pick it up. Um and we actually have a uh a rotenone project uh using iPSC models that my first grad student is working on. Um and again, like you said, um I mean it's it's it's certainly interesting to see whether Parkinson's itself will culminate or or can even culminate in uh the loss of neurons without ostensible sunuclein aggregation, or whether that's sort of required for it, uh or whether there's multiple diseases that all end up um at dopamine neuron loss through various mechanisms, and they're all Parkinson's disease. I don't know.

Akshata 31:13

Yeah,

Drug Development Challenges, the risks and hurdles

Akshata 31:14

yeah, no, that's true. But I'm I'm I'm curious, you've been in the field now for a decade or more, I guess. More. Uh and and I'm just curious from your perspective, like how could we help speed up the drug development, you know, the the innovation of therapeutics for Parkinson's? And and it appears like you know, I've I've transitioned from academia to industry, and I kind of have beginning to appreciate both sides, but I'm also recognizing the crosstalk that's happening is is not maybe there where it needs to be. And I'm curious what your perspective is. Like, what are some of the you know challenges? Also, what are the opportunities in that space?

Nikhil 31:59

Sure, and I think this this answer would would truly benefit from uh from your input also. I have limited industry experience. I actually began my career off in industry, but that was a short stint I did as a as a teenager. Um but um I think biotech is pretty fast-paced, um, which again is great and bad and everything in between, in that you know, ideas can like truly progress at a fast pace. Um, and once you like hit on something, you know, you can get a team together and like truly sort of make a go of things. Um, but it is a bit um, I guess, um I guess whimsical. So it it's more, it's it's it's more prone to sort of changing priorities, perhaps too quickly. And I think if I could um if I could point out uh uh a flaw in in industry, that's what it would be. So sort of, you know, the the the the propensity to sort of give up too easily or change directions. Yeah um and I guess academia from your perspective perhaps is is is somewhat stagnant, you know. So we sort of get fixated on certain ideas and certain things uh and get obsessed and are uh too resistant to to change.

Akshata 33:21

Um I I guess uh honestly from my perspective, I do think that it's amazing that because the the time constraints that sometimes like coming from an industry perspective in in reaching your milestones, if you will, are not necessarily there. Like they're different kinds of pressures, whether it's grant submissions or paper submissions, and you know, but then I think I really appreciate the in-depth because I I guess what the industry is building off of is the basic research. Um, so I do think that that's that's amazing, and I think that the work that's done in industry can can really help then take those and and develop further. But I I do think that sometimes these are siloed, and there's been more consortium works which is helping bring it together, but I I wish there was more, and I don't know if you were in the same camp, or you think that that's that's changed. It's changed over the years.

Nikhil 34:14

I there's it may have changed a little bit, yeah, but I think there's like tremendous uh room for for improvement. Yeah, and I certainly don't think that there's enough um industry, academia, crosstalk. So I mean, occasionally, you know, I'll have um folks in the industry who sort of consult with me about inflammasomes and but but but um I mean why look at inflamasomes and brain disease, right? So so uh uh uh so in in in in my experience, a lot of well, some industry folks tend to sort of pick out hits that they that they think are hot without truly understanding the the biology behind it.

Akshata 34:55

Yeah.

Nikhil 34:55

Um and um in in in academia, I guess I'll I'll I'll I'll leave it to you to pick out what flaws we have, because I'm sure we have.

Akshata 35:06

No, I I do think that you know it it's it's amazing to see the cutting-edge research that you can do, but I did think that some of there were limitations in terms of maybe the chemistry or like you know the way the modalities or like you know way things could be approached or the large screening that you can do because it is and the culture is changing a little bit. I know there are people who are working with chemists within their groups and stuff, and I think that that cross-collaboration across academic groups from very different spheres is certainly helping uh start that now already in academia, but I do think it's not not done to that large extent, which which of course requires a lot of financial support. So I completely understand why, and but I do think that there could be that you know one side coming from academia and another from industry where we could really push this forward because uh obviously these are like not trivial diseases to treat, and and you know, um that that's certainly it, but seems like this is the time in neuroscience where a lot of things are coming along, not only like new mechanisms, as you said in Parkinson's, um, but also you know, different kinds of treatments that are that are coming about. And and you know, like I as you said, there was like stem cell research and uh there's other modalities. I'm actually you know curious, like what what do you think are the problem some of the promising um you know therapeutics out there, or you think might be something that patient families could look forward to?

Nikhil 36:45

Um before I proceed with that question, I I do want to echo what you said back there about uh, I guess cross-field collaboration. And I I I I completely agree with you. So in academia, I think there is a distinct lack of, well, things are siloed sometimes, and there is uh a lack of the cross-pollination of ideas across different departments. And chemistry, I think, is the is the best, uh, the best possible example. So um if if if you find something that's that's that that's interesting and that is potentially druggable, it's certainly makes sense to sort of have uh the input from chemistry saying, okay, here's how we can approach this, and really sort of interrogate your hypothesis. Here's what we can do, and here's what we can't do. Um, and there's some potential targets that really aren't targets at all, uh, certain kinds of kinases and whatnot, but are really not worth investigating in any species, shape, or form because they're simply not not non-druggable, not yet, anyways.

Akshata 37:46

Yeah.

Nikhil 37:47

Um, so yes, uh, I think uh industry does facilitate by its design um an easier cross-pollination of ideas across fields. And I wish we had more of that.

Akshata 38:01

Um yeah, no, and I guess it's great that we are then talking across here and and hopefully like you know, sharing some of this um unbiased opinions, right? Because I do think that there is that need for people to know, like, okay, what is that disconnect? Like, you know, why, because I guess we always think of like, oh, why are these, or at least I've heard frustrations from patient families, um, you know, including mine, where it's like, why is there no drug yet? Right. And and I think that just understanding the feel, like, you know, the heterogeneity, you know, across, like you you mentioned a whole spectrum of like within within Parkinsonianism, like there is all these different patient populations, all of that, along with uh the silos that sometimes are created. And and hopefully we are we are trying to get closer in in um you know reducing those gaps.

Nikhil 38:55

Sure, yeah, yeah. Um, you asked about potential therapeutics that I see on the on the horizon.

Akshata 39:03

Yeah, yeah. On on a more, I guess,

Promising therapies

Akshata 39:07

like what are some of the promising ones that you think? And and then I guess like on a more hopeful note, like you know, that might potentially be game changers in your mind.

Nikhil 39:17

Oh, I I I I am actually hopeful. Uh so let me begin my answer off by saying that. Um, for the longest time, we didn't think Alzheimer's would have any even slightly disease modifying therapy. Of course, that's only in a subset, but even that, um, if you asked us 10 years back, I don't think any of us would have said yes, there's gonna be a any disease modifying therapy. But there is some that, albeit only in a subset, does seem to shift the cost a little bit. So, but it's a it's a start. Um, so I am I am quite hopeful. Um, and so there was this stem cell study done in uh in well, two stem cell studies. I think uh that there was a Japanese group that did IPSC differentiated neurons, uh, and one in California that used ES cells. Uh, but the IPSC work. Um, so like I said, there were studies before wherein people took dopamine neurons from fetal mesencephalic brains and transplanted them into Parkinson patient brains, and those graphs also got Parkinson's. So, you know, it was like, what's the point of doing transplants if the transplanted cells are going to get infected with with protein aggregates? Well, you can circumvent that by just transplanting a much larger population of cells. You know, they all can't get Parkinson's like pathology. Um, so there was this Japanese group. Uh, I think the the paper came out in uh in Nature last month, wherein um I think seven patients were treated with IPSC differentiated neurons. And out of the seven, I think six showed uh an increase in dopamine uptake 48 48, I think, uh or 24 months after injection. Several showed increases in uh in in motor function, some reductions in disease cause, um, and not much microbial activation.

Akshata 41:11

So uh that's that's really exciting.

Nikhil 41:14

Absolutely. Um, so so and again, IPSC cells are unlimited. So it's not like you're curbed or limited by the raw material that you have. So, right, right that that itself, I think, is a pretty major accomplishment. Um, the second, I think, is is the prospect of brain inflammation being drugged in both Parkinson's, Alzheimer's, FTD, and ALS. Um wherein I do think by their by their very nature, um microglial cells or the myeloid cells in the brain are just far more druggable. Um they're more targetable uh with with respect to therapeutic strategies. And I do think that once we begin in earnest to target brain brain inflammation, and eventually that will yield um positive results, uh, at least in hopefully a subset, if not more, uh a large swath of patients. So I am quite quite optimistic going forward. Um, you know, I'm keeping my fingers crossed in these two areas of research.

Akshata 42:23

That sounds, yeah, no, that sounds really exciting. And there has been like really, I guess, some biotech companies and others, I guess, working on the inflammation, which you which you mentioned previously, which I think could be very promising, hopefully not just for Parkinson's, but for other neurological diseases as well. And yeah, now thank you so much. I I think that leaves us on a very hopeful note, and I'm I'm really thankful for the time that you've taken to share with us your research and also like the Parkinson's field and research in general today. I think that um that kind of helps us give a perspective on how the fuel's moving and and also like I guess some of the challenges, but also some of the things we could be hopeful about as this research has has moved forward. Thank you so much, Dr. Panicker.

Nikhil 43:11

Oh, I'm Nikhil. Uh and um I'm super grateful for you having me. And I I I love chatting. Uh, thanks much for the opportunity, and yeah, thanks for having me.

Akshata 43:22

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