Mutations in LRRK2 are the most common genetic cause of Parkinson’s disease. Here, Claudia Manzoni talks about her research (funded by the Rosetrees Trust and the Michael J. Fox Foundation) into what LRRK2 might be doing within the cell: Parkinson’s disease is a brain illness that afflicts 1 in 500 people in the UK. High profile patients, such as the actor Michael J Fox, the boxer Muhammad Ali and the late Pope John Paul II, have raised public awareness of Parkinson’s and its devastating impact.
Parkinson’s disease attacks a small area in the brain called the substantia nigra (located in the very middle of the brain). This part of the brain controls voluntary movements so when it is damaged by Parkinson’s disease, the patient loses control of his or her movement. At the start of the disease, patients might notice one of their hands trembling a little, but over several years the symptoms dramatically increase, accompanied by a progressive slowing of all movement, until the point where walking and talking become severely impaired and the fine control of precise and small actions, like moving the fingers to tie the buttons of a jacket, is completely lost. Although we have some drugs that can treat the symptoms of Parkinson’s, we have no therapy that actually slows down the disease or prevents it running its course.
For the vast majority of patients, there is no explanation as to why they develop the disease. However, in a very small number of cases some close relatives are or have been affected by the same condition. These rare cases are called familial Parkinson’s disease because, literally, the disease is passed down through the family. The reason for this is because there is a mistake in the DNA that provides the genetic blueprint for each and every one of us . The most common spot where these mistakes (called mutations) concentrate in Parkinson’s disease is around a stretch of DNA that contains the information for the production of a protein LRRK2 (pronounced “lurk two”). LRRK2 is a cellular component called an enzyme. An enzyme is a microscopic machine able to carry out tasks for the cell. Thanks to the information stored in the genetic library, a single cell produces tens of thousands of different machines that permit it to function. When the LRRK2 machine is altered by a mutation, the process that leads to Parkinson’s disease starts.
The idea driving our research is that, if we succeed in understanding what jobs LRRK2 performs within the cell, we will then have an idea of why a mistake in LRRK2 has the power to cause Parkinson’s disease. Crucially, this information might be the first step towards finding pharmacological treatment to fix the alteration and prevent the disease happening in the first place. This will also give us precious information on how to study Parkinson’s disease when it is not related to any mistakes in the genetic library; at the moment we find very hard to approach this kind of studies because we do not have idea of how and where to start investigating.
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We were interested in looking at whether LRRK2 is involved in a process called autophagy, a word coming from the Greek “auto = self” “phagein = to eat “, literally “self-eating”. Although it sounds slightly macabre, autophagy is, in fact, a vital cellular process that allows the cell to keep itself clean and smart. During its day-to-day functioning, cells produces waste; autophagy is the process through which the cell “eats” and destroys all that rubbish. There are machines in the cell able to sense the presence of waste and others that are able to locate and collect it. And as in a large city like London, there are many large (and small) waste disposal authorities within the cell, but the principal one is called m-TOR. Once the waste is collected there are machines that are trained to surround it with an envelope made by a thin film of fat creating a droplet full of rubbish floating inside of the cell. This drop is then internalized by cellular organelle called lysosomes that works for the cell as the Edmonton incinerator does for the city of London. The lysosome is able to “burn” the drop of rubbish and destroy any single molecule into elementary pieces that can be used to recover energy or to build something new.
Based on previous experiments by several groups of scientists around the world, we used a drug that has been formulated to bind LRRK2 and to block it in a conformation that stops it functioning normally. We grew human cells in a Petri dish and we then treated them with that drug. Surprisingly, we found that autophagy was strongly stimulated by this treatment. By blocking LRRK2 a massive and unnecessary increase of waste collection and disposal was induced.
This led us to the conclusion that LRRK2 has a role in autophagy. However, there are many steps in the process of autophagy, from the recognition of the waste to the actual destruction of it and LRRK2 could be intervening anywhere along the process that leads to waste disposal. The next step was then to figure out at exactly what point LRRK2 is involved. We started by excluding the possibility that LRRK2 works at the end of the process, in the actual disposal. From the data we have collected, it is more likely for LRRK2 to be involved in autophagy as a disposal authority, responsible for the regulation of the process at the very beginning. Although the main disposal authority is m-TOR, we found that LRRK2 works independently of it – probably managing a smaller and parallel service. Now we are actively working to identify all the cellular components that “work” for LRRK2 to manage the waste disposal and so far we demonstrated that even if m-TOR and LRRK2 run independent businesses, they communicate and share at least one of the same contractors that are able to start wrapping up the waste.
We are working to clarify all the details of LRRK2 function, and after that even more work will be needed to determine how its function is altered in Parkinson’s disease. However the good news is that even if we are still very far from a complete picture of what causes Parkinson’s disease, we are making progress by piecing together some of the clues that genetics has given us.
Manzoni, C., Mamais, A., Dihanich, S., Abeti, R., Soutar, M., Plun-Favreau, H., Giunti, P., Tooze, S., Bandopadhyay, R., Lewis, P., 2013. Inhibition of LRRK2 kinase activity stimulates macroautophagy. Biochim Biophys Acta.