Maddie Kyrke-Smith

Large networks of strongly connected neurons form the structural basis of healthy brain functions. From our motor skills to our memories, these neural networks define who we are and what we do. Further, degradation or loss of neural networks is implicated in a vast array of neurodegenerative diseases and conditions such as Alzheimer’s disease. So how does a healthy brain maintain its networks? And how could our understanding of the processes that maintain these networks be used to treat neurodegenerative diseases? These questions formed the basis of the 2015 Roche Hans Möller Doctoral scholarship winner Madeleine Kyrke-Smith’s PhD thesis.

One of the most important mechanisms in the formation and maintenance of neuronal networks is called long-term potentiation (LTP). LTP is a process by which functional connections between neurons, called synapses, are strengthened. Changes in the expression of specific genes have been shown to play a key role in LTP maintenance, and in maintaining the structure of neuronal networks. However, Madeleine wanted to extend this understanding by studying epigenetic enzymes which limit gene expression; enzymes called histone deacetylase 1 (HDAC1) and 2 (HDAC2).

Madeleine’s work found that both HDAC1 and HDAC2 were particularly active during the early stages of LTP, where the connections between neurons are initially strengthened. Further, when testing a potential therapeutic agent which inhibits HDAC1 and HDAC2, to alleviate their negative regulation of gene expression, Madeleine found LTP could be enhanced for over a week. However, HDAC1 and HDAC2 didn’t appear to be more active or involved in maintaining those connections over a longer timeframe. Her findings have identified a distinction between processes involved in the formation and maintenance of neuronal networks. This implies that therapeutic agents should be targeted to specific mechanisms at distinct time points, as enhancing the initial stages of network formation may not translate to the maintenance of those networks over time. This is important for conditions such as Alzheimer’s disease as the effectiveness of HDAC1 and HDAC2 inhibitors may be limited to assisting in the formation but not maintenance of new memories, whereas it is in fact the maintenance rather than formation of memories that is severely impeded in this condition.

Hannah Best

Batten disease is a group of inherited neurological disorders that usually present in previously healthy children, presenting with clinical symptoms similar to epilepsy, blindness, Alzheimer's and Parkinson’s disease. The exact changes that occur during disease are not fully understood, making it difficult to design therapeutic strategies. Currently there is no cure, although several preclinical and clinical trials are showing great promise for some disease forms. At the University of Otago, we use sheep and mice with naturally occurring mutations in two Batten disease associated genes, CLN5 and CLN6, to further our understanding of disease pathways, and to inform potential therapies.

We have identified a range of disease-associated changes in isolated sheep brain cells. These include: reduced cell size, altered morphology, reduced uptake of material by cells, defective waste removal, and reduced cellular acidity. These changes are subsequently used as markers of disease, and therapeutic strategies tested for success via their ability to ‘correct’ these markers.

Based on the success of correcting disease markers in isolated cell culture, two therapeutic trials have been initiated, and are nearing completion in the CLN6 mouse model. Firstly a small molecule drug aimed at enhancing cellular waste clearance, and secondly a gene therapy approach aimed at reintroducing gene products that are decreased in the disease. This research has shed light on the cellular basis of disease, and has the potential to substantially inform a cure for this fatal, debilitating illness.