Nematode genetic variation and protein misfolding disease

Dementia is an increasing global concern. Whilst details of the causes of dementias occurring in Parkinson’s disease, Alzheimer’s disease and Huntington’s disease differ, they are linked by incorrect protein folding – proteins are altered from their normal state, accumulate and form large insoluble masses. 

To improve the outcome for dementia, we need to lower incidence, improve treatment and prevent or slow disease progression. This requires that we understand the factors that determine who develops disease, and how quickly that disease then progresses. We understand some of this, but many questions still remain to be answered. Particularly important is to identify and understand the genetic differences between people that affect both incidence and disease progression. 

Genetic variation is systematic and pervasive, with millions of genetic differences present between any two human genomes (identical twins notwithstanding). Such genetic variation can affect the action and effects of other genes. At the extreme end of this are healthy people who carry mutations that would be expected to produce severe disease. As they have not developed these diseases, they must have genetic variation elsewhere in their genomes. More generally, many genetic variants will have more subtle effects on susceptibility to disease, disease progression, and how someone would respond to a drug. 

Animal models, such as the nematode worm Caenorhabditis elegans, have an important role to play in understanding dementia. This worm was the first multi-cellular animal whose genome was sequenced and it has been important in developing our understanding of many fundamental aspects of biology. The great majority of work on the worm has however been undertaken using just one single genotype – something that is tremendously powerful for some approaches, but not helpful if you are interested in natural variation. 

In this project I, and my co-investigator Dr Lee Byrne, are seeking to understand how genetic variation within C. elegans affects the onset and progression of Parkinson’s disease and Alzheimer’s disease. We will take two complementary approaches to achieving this. Firstly, Parkinson’s and Alzheimer’s disease transgenes, human genes associated with the diseases that have been introduced into the worm genome, will be crossed into different C. elegans genetic backgrounds. This will create new lines of worms with new combinations of natural genetic variation. These lines will be assessed for variation in the onset and progression of pathology. Secondly, regions of the worm’s genome that affect variation in native protein aggregation – a normal age-related process characterised by increased protein misfolding in older individuals – will be identified. The effect of these regions on the Parkinson’s and Alzheimer’s disease transgenes will then be assessed. 

In combination, our experiments will identify genetic variation in C. elegans related to Parkinson’s and Alzheimer’s disease, and will tell us if this variation is linked to other characteristics of the worms. By looking at variation in response to both Parkinson’s and Alzheimer’s disease genes, and at native protein aggregation, I hope we can identify general solutions to protein misfolding disease. Ultimately, I would like to isolate the specific genetic differences that underlie this variation, and the completion of these objectives in this project is the necessary first step to achieving this. 

Dr Simon Harvey
Canterbury Christ Church University
Research Project Grant

Above: adult worm expressing a human Parkinson’s disease related gene that is linked to a fluorescent marker. This results in age-related aggregations of fluorescent protein that can be counted. To assess the effect of genetic background on disease progression our newly created lines can be compared for the levels of fluorescence, the number of aggregations and how these things change as they age. Other aspects of worm health, such as fecundity and lifespan, can also be assessed to determine how they relate to these measures. Image credit: Simon Harvey and Dr Katie Fowler, CCCU.