Rogier Burggraaff, medical student

I’m a 23-year old medical student at the University of Groningen. From November 2009 to April 2010, I did a six-month internship at the Department of Genetics, UMC Groningen, in the research group of Ellen Nollen as part of my course. This group is working on neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease. They are aiming to identify genetic modifiers of aggregation: the clumping together of certain proteins, because aggregation is believed to be central to the pathogenesis of many neurodegenerative diseases.

At the start of my internship, a new gene that strongly influences this process of aggregation had just been identified. My project was to investigate whether this new gene, modifier of aggregation-4 (moag-4), exerted its strong influence on aggregation through genetic pathways known to be involved in protein aggregation, or not. To do this, I used the model organism C. elegans, a worm which has about 60% of its coding DNA in common with humans.

I had a very good time doing research in this group. At first I found myself a bit overwhelmed with all the new information, because I did not know much about genetics or cell biology, nor did I have any serious lab experience. However, the more you get to learn about these things, the more intriguing it gets. Right now, I am preparing to apply for an MD/PhD scholarship to continue research into the genetics of these neurodegenerative diseases in combination with my clinical rotations (co-schappen).

Report -Summary

For an increasing number of neurodegenerative diseases, like Alzheimer’s disease, Parkinson’s disease and polyglutamine disease, e.g. Huntington’s disease, the aggregation of misfolded protein is thought to play a crucial role in the neuropathy. Recently, a new gene has been identified in a Caenorhabditis elegans (C. elegans) model for polyglutamine aggregation, called modifier of aggregation 4 (moag-4). Inactivation of moag-4 suppressed aggregation by 75% and reduced polyglutamine toxicity. These effects have been replicated in C. elegans models for aggregation in Alzheimer’s disease and Parkinson’s disease. Moreover, moag-4 has two human orthologues, Serf1a and Serf2, which in cell culture show a similar effect on aggregation and toxicity of mutant huntingtin. It is unknown how moag-4 influences aggregation. We hypothesized that moag-4 acts on aggregation through downstream targets.

In order to investigate this, we performed an RNA interference screen, in which we knocked-down selected genes that have been previously associated with protein aggregation and determined whether they could reverse the effect of moag-4 inactivation, which would indicate that moag-4 acts through these genes. We included genes coding for transcription factors of the insulin/IGF-1 signalling pathway, heat shock proteins, components of CCT chaperonin, predicted chaperones, the ubiquitin-proteasome system and C. elegans orthologues of genes associated to aggregation in other species. In none of these genes could knock-down rescue the suppression of aggregation by the loss-of-function of moag-4. These findings strongly suggest that moag-4 acts independently of genes known to influence protein aggregation in C. elegans and it might therefore represent a novel pathway in protein-folding and neurodegenerative diseases.