Okay, so C9orf72 hexanucleotide repeat expansion is, in fact, the most common genetic cause underlying both frontotemporal dementia and amyotrophic lateral sclerosis. Why we are interested in that is that this repeat expansion is exceptionally common here in Finland, in our FTD and ALS patients so we became interested in that. Basically what it means is that the repeat expansion or the repeat sequence is present in all of us, but in the patients, the repeat sequence gets expanded hundreds or even thousands of times and this is thought to underlie the disease pathogenesis in these patients...
Okay, so C9orf72 hexanucleotide repeat expansion is, in fact, the most common genetic cause underlying both frontotemporal dementia and amyotrophic lateral sclerosis. Why we are interested in that is that this repeat expansion is exceptionally common here in Finland, in our FTD and ALS patients so we became interested in that. Basically what it means is that the repeat expansion or the repeat sequence is present in all of us, but in the patients, the repeat sequence gets expanded hundreds or even thousands of times and this is thought to underlie the disease pathogenesis in these patients. There are kind of three main hallmarks that we can find in the patients. One is that the normal expression of the C9orf72 gene is lost because of this repeat expansion. But then also there are toxic RNA and protein products that are produced from the repeat expansion sequence itself and these are thought to be harmful, of course, for the neurons and cells in the brain and are thought to underlie the neurodegeneration then seen in these patients.
Okay. So we have been interested in investigating these protein degradation pathways in cells, and we have particularly concentrated on two pathways. One is autophagy and the other one is the ubiquitin-proteasome system. So we have previously studied these pathways in different model systems and in the model systems that we have used, which have been mostly like neuronal cells or microglial cells, we have found that knocking down of the C9 gene, modeling the sort of the situation in patients where this normal expression of the gene is decreased by this expansion, we found that this knocking down of the C9orf72 gene leads to an impairment of autophagy. Whereas in other models where we overexpress the pathological repeat expansion sequence itself, we didn’t really find much differences in the autophagy or the proteasomal system. So at least in these systems where we have used, it seems that the loss of normal function of the C9orf gene seems to be especially important for C9orf72 protein to function in these pathways.
But however, these have been very sort of acute models and we know that some of the brain pathological changes that may be caused by defects in these proteasomal degradation pathways in patients take years or even decades. So definitely, of course, if we were able to use different types of models, we might find some different results as well. But this is what we have found in these kind short-term models of ours.
Of course, we would be interested in next looking at how the repeat expansion in the C9orf72 gene affects these degradation systems in human cells. And we are currently generating these pluripotent stem cell-derived neurons and microglia from C9 expansion carrying patients and we aim to assess these pathways in these cells next. Then we shall see what kind of findings we will have in the future in these human-based models.
