MND and Me Fat Rabbit Research Grant – Update May 2019 – MND and Me Foundation

MND and Me Fat Rabbit Research Grant – Update May 2019

Recipient: Dr Sean Millard

Identifying molecular pathways disrupted in sporadic ALS

Our lab is trying to understand the function of genes that cause ALS. In collaboration with Prof Naomi Wray’s human genetics laboratory at the Institute for Molecular Bioscience, we are manipulating candidate ALS genes in the fruit fly. Most of the proteins encoded by these genes are well-conserved in flies and this suggests that their roles in neurons will also be conserved. We can thus mutate or misexpress these genes in our model system and assess how this affects neuronal morphology, connectivity and survival.  

 

The Fat Rabbit Grant is focussed on a gene called GGNBP2. The Wray group demonstrated an association between this gene and ALS through human genetic and gene expression studies. These studies suggest that GGNBP2 is expressed at higher levels in people with ALS compared to control groups. We have therefore been manipulating the fly version of GGNBP2 to try to figure out what it does in neurons. When we overexpress it in motor neurons, they form more connections compared to controls. In contrast, when we remove it, motor neurons form fewer connections. This is the first indication that GGNBP2 plays a functional role in motor neurons and that the levels of this gene must be tightly regulated.

 

GGNBP2 was identified in the sporadic form of ALS. In contrast to familial ALS, where mutations in a single gene lead to disease, sporadic ALS results from defects in several genes that together increase risk significantly. To explore this in our system, we are combining GGNBP2 with other ALS risk factors to determine whether the combination of mutant genes results in earlier onset of degeneration or more severe pathology. We do these experiments in the fly eye as it is not essential for viability and offers a clear readout for neurodegeneration. We have found that overexpression of GGNBP2 in combination with another ALS gene significantly enhances degeneration compared to either gene alone. In the Fat Rabbit grant, we are assessing the gene expression changes that take place when both risk factors are present. We are currently optimising the timing of the degeneration so that we can isolate tissue before excessive cell death is occurring. This will allow us to identify changes in gene expression that induce cell death rather than gene expression changes that carry-out the cell death process (which are already well described). The goal is to identify molecular pathways that lead to neurodegeneration as these will be candidate drug targets.