In Parkinson's disease, different from Huntington's disease, which is 100% genetic, Parkinson's disease is not. PD is very much like Alzheimer's disease. There's about 12% plus or minus, that are familial, therefore, genetic. There is about 85% to 88% of the patients who are sporadic, means we don't quite know, yet, okay. And in PD, there's more than one gene already found. For example we, just number those genetic forms park1, 2, 3, 4, 5, 6, just on and on. So I listed here those genes that are already identified as Parkinson's disease genes. Part1&4, the gene is alpha-synuclein. Park2 is Parkin. Park3 is a different one. And Park5, UCHL1. Park6 is PINK1. Park7, DJ-1. Park8, LRRK2, and so on and so forth. The mode of inheritance could go from a typical dominant transmission to a typical recessive and in between, they are incomplete penetrance. How early are the diseases onsets depends on each of the genes. For example, Park2, it's a quite typical early onset PD, whereas for example, Park8 is more of a classic one, which means it's a late onset. People thought about this and say, they hoped that we can have situation resembling Alzheimer's disease in which disease gene of proteins are acting on one pathway, right? Remember in AD, we have three genes. Their products are all acting on producing APP, cutting APP into a beta. We hope so, but to our disappointment, in Parkinson's disease it's not. These genes encode in proteins and the protein functions seams to be every where inside a cell. We just don't know. Now, I group that for you in one way of looking at that. I put alpha-synuclein as one example of protein over production. Because, in alpha-synuclein, you can have mutation or you don't have a mutation, just a chromosome duplication of wild type alpha-synuclein. Gives you the same Parkinson's disease. So it's a protein load increase that's causing the disease, right? The other side of the same coin is protein degradation. Our cells need to constantly take out the garbage, just like our campus or our building. You need people to sweep away those garbage. In the cells, do that in two main mechanisms. One is called the proteosome pathway. The other one is lysosomal autophagy pathway. This proteosome pathway is one of the typical ones that a protein's degrade in. What it does is, our cells are very smart, so they, when a protein is to be degraded, they will put tags on it. And that tag is ubiquitin, [FOREIGN]. They will put tags on this protein with a [FOREIGN] chain, ubiquitin chain. That labels a cell, drags it to the proteasome. Proteasome is a wonderful structure, it's like a cylinder, okay. In the middle of the cylinder, that's the scissor. So proteins to be degraded, labeled by ubiquitin will first unfold, is no longer a globular structure, it's now almost linear. And then, this linear thing will be sucked in to that proteasome cylinder, just [SOUND] come in. And here is a scissor, it just cuts, cuts, cuts, cuts, cuts. So that's how a protein is degraded in this way. The funny thing is that our cells are very economic, stingy. We don't waste things. So after killing that protein, we actually reuse the ubiquitin. There is an enzyme that breaks this ubiquitin chain into monomers. And that enzyme is UCHL1. Okay, now in Parkinson's disease, we have already found two proteins that are mutated, two genes mutated in this context. The first one is Parkin. Parkin is an E3 ligase, that adds your ubiquitin to protein substrates. Mutations in Parkin or deletions in Parkin causes Parkinson's disease. The second one is UCHO1, the enzyme that reuses ubiquitin. Therefore, in all the genes found, two are in the same pathway. That's a quite powerful argument for the hypothesis that protein degradation abnormality accounts for a big part of PD development. That's the human genetic support. Parkinson's disease, I want to mention, it's actually a collection of diseases. What we usually refer to Parkinson's disease is the very first one. It's primary PD or in medical term, it's called idiopathic PD. We have other forms of Parkinson's disease. For example, Parkinson's Plus, including PSP, CBD and MSA. We have secondary Parkinsonism, which is drug induced or sometimes, trauma induced. We know boxers. [FOREIGN] has really, really high prevalence of Parkinson's disease. And unfortunately for you guys who like to play soccer, professional soccer players have much higher PD preference. Okay, now, what we usually talk about PD is the first one, so I will stick to that. Park6, PINK1 is something I want to mention to you briefly, because this is the first one ever that indicates mitochondria dysfunction. It's not only pathologic, it could be pathogenic in neurodegeneration Why do we say that? Here's the reason. Because mitochondrial dysfunction has been found in almost all neurodegenerative diseases. It's also found in normal aging. Meaning, if you take my mitochondria at age of 20, 40, 60, 80, 100, I hope I can live to 100. >> [LAUGH] >> If you can measure the functions of mitochondria in their ability to make a TP, in their ability to quench ROS and all that. You will see obviously, the 20-year old is really, really robust, and the 80-year old, or 100 year old, goes down, without any disease. In diseased brains, it's much more so. However, just like our TA indicated, we don't know whether it's a cause or simply an effect, right? This PINK1 solves that puzzle by providing one piece of evidence because PINK1 gene is a nucleus-encoded gene. And this nuclear-encoded protein is transported right away into mitochondria. Therefore, in human genetics the mutation in PINK1 causes PD. And the only way it can induce a disease is somehow, something is abnormal in mitochondria first. Right? It's the first case, and so far, it's the only case that is so clear. Microcondria deficient in PINK1 patients has to do with the initial hit.
