Skip to 0 minutes and 2 secondsAgeing, defined as time-dependent functional decline, is common to all living organisms. It's a complex process and poorly understood. One of the main hallmarks is the increase of protein misfolding and the appearance of protein aggregation in the brain, linked to some age-related disorders like Alzheimer's, Parkinson's, or Huntington's. So let's go to the brain to understand how protein aggregation occurs. Under normal circumstances in the neurons, the proteins are translated by the ribosome. And at the same time, they have to be folded to get their native and functional confirmation.
Skip to 0 minutes and 43 secondsBut who's helping to fold the proteins? These factory workers are also proteins called chaperones. And they have a main role for the proper folding of the proteins. Sometimes these proteins are defective. And the chaperones cannot fold them correctly. Then these defective proteins will be degraded and recycled by the proteasome or the lysosome, which are very important for the maintenance of the proper function of our factory. All these workers working together is what we know as the protein quality control in the cell. During ageing, there's a decline of this protein quality control, which increases the failures of the folding of the proteins that will get stuck in our assembly chain, leading to a general failure of the factory.
Skip to 1 minute and 27 secondsAnd this is how the protein aggregates are formed in the brain under disease conditions. Some neurodegenerative diseases are characterised by the constant production of certain defective proteins, being more necessary the correct and efficient function of our workers to avoid the general factory collapse. But what happened when these diseases are combined with ageing? But how can we study the aggregation process in an easier way? Well, to do that, we can use model organisms. These are simpler organisms that allow us to address very complex questions in an easier way. And our model organism is called C. elegans. It's just a worm which lives in the soil. It has some features that simplify a lot of our work.
Skip to 2 minutes and 15 secondsFirstly, it's lifespan is very short. So we can study age-related processes in a time lapse of only three weeks. In addition, the neuronal system in these worms is very basic, comprising only 302 neurons. However, the protein quality control also exists here. And it's very similar to that in humans. But there is a last characteristic which makes our worm very special. And this is that they are transparent. Thus, we can fluorescent label any protein of our interest and visualise it in vivo. What would happen if we take the defective proteins into the worm, and we label them with a green fluorescent molecule, GFP? Yes, we can see how the aggregates form.
Skip to 2 minutes and 58 secondsAnd we can follow them during ageing, making the worm a good model to continue our study. Now we can use our model to look for other proteins involved in the aggregation process. This will help us to understand how this mechanism works, and to design potential treatments against the toxicity of the aggregates in the brain. But how can we do that? Well, to do that, we have to do a very bad thing. We have to create mutant worms. Yes, sorry. But not the Frankenstein mutant kind. The mutants we are looking for have less aggregates. This means that the disruptive proteins in these mutants promote the aggregation. This is how we found MOAG-4.
Skip to 3 minutes and 39 secondsWe showed that MOAG-4 is able to drive aggregation for three different disease proteins involved in Alzheimer's, Parkinson's, and Huntington's. We still don't understand completely how MOAG-4 works. But what we know is that this protein is widely distributed in nature, and that the human counterparts are called Serf 1A and Serf 2. These two human proteins have been shown to play the same role as MOAG-4, driving aggregate formation. This would suggest the idea of the inactivation of Serf 1A and Serf 2 would protect against neurodegenerative diseases, making them good candidates for the development of treatments.
A worm to understand the diseases of ageing
Some diseases of the human brain – known as neurodegenerative disorders – show an increase in the production of misfolded proteins and the formation of protein aggregates.
These late-onset diseases are characterised by an overloaded and failing system of protein quality control. Why this system is gradually falling short, and how this can be prevented, needs better understanding.
In this animation, the worm Caenorhabditis elegans will be introduced as a model organism to study protein aggregation in neurodegenerative diseases. The outstanding features of this model were instrumental in the identification of genes that drive the aggregation of proteins involved in the diseases of Alzheimer, Parkinson, and Huntington. Could inactivation of the human counterparts of these drivers of protein aggregation protect us from neurodegenerative diseases? In the lecture following this animation, Ellen Nollen will discuss in more depth her research on protein aggregation and toxicity using the C. elegans model.
© University of Groningen / University Medical Center Groningen