Motor neuron transport physics + TDP-43 traffic jams

1:41:49>> They can be about a meter long. A mele that's 3 ft. >> Oh wow. >> A single cell >> is the size of like 3 ft. >> Okay. >> If you think about it, it kind of makes sense, right? Because um think about your spinal cord, like the lumbar spinal cord. >> Sure. >> A single cell body is going to be located in the spinal cord, but it's going to relay signal all the way down to the foot. >> Yep, that makes sense. >> Okay. That's a single motor neuron that's doing it. >> Okay. Okay. [snorts] Now, maintaining this kind of architecture over an extremely long distance requires moving a massive amount of physical cargo >> from one end of the cell to the other, right? You're going to have to move proteins. You're going to have to move

1:42:29mRNA from your nucleus if you want to like, you know, make make it all the way out there. You have to move mitochondria. You have to you move synaptic vesicles, which are like the acetylcholine and the neurotransmitters. That's got to move. All of that stuff has to move across a meter, a yard worth of stuff, >> right? >> That requires a lot of energy and it requires a lot of motion from these molecular motors. They're called chinesin. >> These kynines are like little tiny molecular motors that actually step in 8 nanometer steps. >> Oh, >> on our microtubules. They're incredible machines that literally take up ATP

1:43:10which is like the energy currency of our cell and each ATP they take up require gets them 8 nanome across. >> Mhm. >> Now 8 nanometers that's 8 * 10 the 9 m. If I want to traverse a meter worth of stuff for a single molecule that's on the order of 10 the 8 >> Mhm. >> ATP molecules that I need to hydrarolyze. Y >> right. Y >> it requires a lot of energy. >> Okay. And when you have a lot of ATP that's being built up and something is wrong in the genetics of that neuron, you're going to get an accumulation of misfolded proteins. Specifically, one of the main ones is TDP43. It's a misfolded

1:43:50protein that causes physical blockage and traffic [clears throat] jams >> on these highways of transport, >> right? And when you have that traffic jam, you're going to get into an energy crisis because now your mitochondria are unhappy. They don't have the actual raw materials. They're the factories that create, you know, the the powerhouse of the cell or whatever. They're the factories that actually create this ATP. You're going to not have them being happy. Those guys are going to create reactive oxygen species, which are just like byproducts with oxygen. Oxygen is just like something that wants to react with everything. And so it's going to cause effectively like rust >> in your neurons. The same way that iron

1:44:31rusts in atmosphere, if you don't have the correct machinery to regulate the reactive oxygen, that reactive oxygen is go going to go and go haywire in your neurons. >> The the other analogy for this would sort of be on that highway. It's just like you're getting potholes over time that never get fixed. So you don't have do department of transportation coming through and fixing it and then it just deteriorates over time to a point where you can no longer traverse. >> Exactly. It's this thermodynamic breakdown. Right. And ALS is like a macroscopic manifestation of that thermodynamic breakdown. You're right. The neuron can literally not maintain its highly ordered state because the mitochondria is doing all sorts of crap.

1:45:11The >> the genetics is not being good enough to keep that low entropy state alive. >> Right. Right. Right. And so and so you're getting >> just massive amounts of failure everywhere >> for these motor [clears throat] neurons. >> And the point is this is something that's it's un it's like it's across your your whole system. >> Yeah. The entire motor neuron like is just like >> Right. Yeah. >> Right. >> Now the muscle's not so much but the motor neuron is like the wire >> that is sending the muscle the signal. >> Yeah. Right. >> Yeah. >> It's like like in your car when your computer goes down. >> Yeah. the it you turn it however much you want. The engine could be fine. >> Fine. The engine's still fine. It may

1:45:51not be, but the engine's still fine. And but the problem is you don't have >> but like but like your spark plug or whatever like there's no electricity going there to do anything. >> Yeah, that makes sense. >> You know? Yeah. >> So, so that's that's the problem. It's the motor neurons that are that are that are really just >> from overuse and from degradation are not working properly. Mhm. >> And there's been a translational chasm in drug development. >> It's not been good. >> Okay. >> We've been as humanity incredible at solving medical problems. ALS is one where historically it's just been beating us. >> Yeah. >> And it's been crazy, dude. Like there's the example of failed drugs. Like

1:46:31there's so many failed drugs because they all show pre-clinical promise in like rat models and mouse models, but then when you get to humans, it's all failed. These are just some of the many there's >> I think something like a more than a hundred that fail preclinical that pass the pre-clinical stage in mouse models. >> Yep. >> But then when it go comes to humans, it's just all failure, failure, failure. Okay. And what does that say? What that says is we don't have a good model in the lab to test drugs for ALS, >> right? Because the the point here is is for a variety of things,

1:47:12>> we can use these rodent, mouse, rat model. We can use them as the test bed and >> there's so many where it works. That's why we do research on >> it. It just works fine and it's fantastic. It does not work for this. >> It does not work for ALS. There's something fundamentally different. And what we need is in lab a model that we can actually test drugs on. >> Right. Right. That that that translates post preclinical into actually looking >> into actually the clinical trials. >> And this is where the um