 Eucalypidosis type 4, or ML4, is a genetic disease that is found primarily in the Ashkenazi Jewish population. It is characterized by neuronal degeneration, meaning death of neurons, the cells that allow the brain to function. ML4 is very debilitating and patients with this disease suffer from visual impairments, mental retardation and delayed motor milestones, among many other symptoms, which means many of them are unfortunately wheelchair bound. ML4 is part of a group of diseases called lysosomal storage disorders, which are all characterized by accumulation of material inside cells that we call storage bodies. It is thought that the storage bodies are causing the death of the neurons. ML4 is caused by a mutation or a change in the DNA sequence that codes for a protein called mucolipin-1. The mutation makes a non-functional mucolipin-1 protein, which causes ML4 disease. So what does mucolipin-1 do and how does its dysfunction cause this disease? Mucolipin-1 is a protein that is localized to a compartment inside cells called the lysosome. In the lysosome, mucolipin-1 spans the membrane and controls the flow of ions in and out of the lysosome, including sodium, iron, potassium, calcium and hydrogen. Because lots of things happen in the lysosome that require a very specific concentration of certain ions, mucolipin-1 is important to establish this environment and to allow the lysosome to perform its intended function. So what is the function of lysosomes? Well, lysosomes can be seen as the recycling center of the cell because they process unwanted material into substances that the cell can use. So if mucolipin-1 is defective or absent, the environment of the lysosome is not optimal to perform these recycling functions. This defect in recycling debris is thought to be responsible for the accumulation of the storage bodies that accumulate in ML4, but this hasn't yet been proven. So it is important for us to understand what mechanisms could be causing the accumulation of these storage bodies in ML4. That is exactly what the scientists of this paper wanted to examine in an article titled Microtophagy is Defective in Mucolipin-1 Deficient Mouse Neurons, published by the Sloganhop Lab at Massachusetts General Hospital and Harvard Medical School in November 2010 in Neurobiology of Disease. These scientists used a mouse model for ML4 where the mucolipin-1 DNA sequence and protein were removed. These mice have a lot of the same symptoms as ML4 patients, so it's a great model in which to study the disease. Because ML4 is a neurodegenerative disease with the death of the neurons, the scientists studied the neurons isolated from brains of diseased mice compared to non-diseased mouse neurons in a petri dish. The scientists found the same types of storage bodies in neurons in a petri dish compared to the mouse brain, and those storage bodies are also very similar to storage bodies found in ML4 patients. So this was a great validation that the human ML4 disease was very well recapitulated in this cellular model. So what could be causing the accumulation of these storage bodies in ML4 neurons? As I previously mentioned, mucolipin-1, the protein that is non-functional in ML4, is important to provide the ideal environment for the lysosome to degrade and recycle debris to provide a material that the cell can use. One pathway that uses the lysosome to degrade and recycle material is the macroatophagy pathway. The macroatophagy stands for self-eating, which is exactly what it is. Material that the cell doesn't need or that doesn't work anymore gets engulfed in a large bubble or vesicle that will fuse with lysosomes which will degrade and recycle the basic components that the cell can use as building blocks to produce other materials. So the scientists were interested to see if this pathway was functional or not in ML4 neurons. What the scientists found was that the vesicles that carried the material to be degraded did not fuse with the lysosomes because they could not be degraded these vesicles accumulated in ML4 cells, proving that this macroatophagy pathway could not function properly in ML4 neurons. So what did this study show? Although previous studies had looked at the macroatophagy pathway in human cells that are found throughout the body, no one had studied what happens in the neurons in ML4 disease. This study showed for the first time that ML4 neurons have a defect in the macroatophagy pathway which causes accumulation of vesicles because the vesicles cannot fuse with the lysosome and be broken down. This study also established a model to study a very relevant tissue in ML4 disease, the brain, by isolating neurons in ML4 mice which are very similar to the human disease. These cells will provide a great way to look for drugs that can reduce the number of storage bodies or vesicles which may improve survival of the neurons and ML4 symptoms. So what does this mean for you? Because ML4 is part of a family of diseases, the results of this study can also provide the basis for understanding other diseases in the family. Maybe the microatophagy pathway has come into lysosomal storage diseases in general and it certainly seems to be the case based on other studies. In addition, genetic diseases such as ML4 often identify new roles for proteins. So studying genetic diseases can provide clues as to what causes the disease and how we can treat it but also provide an understanding of the role of proteins in normal biology in the absence of a disease. So understanding normal biology is just as important as understanding biology in the context of disease. There's still questions that remain however. Why can't these microatophagy vesicles fuse with the lysosomes in ML4? Is the buildup of these vesicles causing an accumulation of toxic material that is killing neurons? Are these microatophagy vesicles part of the storage bodies? And are the storage bodies responsible for the neurodegeneration in ML4? Or are they protective by containing harmful substances? So as you can see, mouse models have provided a great way to study diseases such as ML4 by giving scientists the ability to study relevant tissues, in this case the brain, that would be impossible to do with patients. Studying rare genetic diseases such as ML4 provides insight into everyone's biology by dissecting out new functions of existing proteins. The findings presented here were funded in part by the ML4 Foundation. This video has been provided to you by Eureka Science. To stay in touch with Eureka Science, like us on Facebook, follow us on Twitter, subscribe to our YouTube channel, or visit us at www.eurekascience.com. Thank you for watching.