Carpenter, Jenna Colette; (2020) An investigation into the mechanisms of Progressive Myoclonic Epilepsy and Ataxia. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Progressive myoclonic epilepsy (PME) is a rare and severe epilepsy syndrome that is caused by mutations in a diversity of genes. The syndrome is characterised by core symptoms of myoclonus (muscle jerks), epilepsy and progressive neurological dysfunction, occurring after a period of apparently normal brain development. Although the genetic causes of PME have been well studied, the underlying mechanisms remain poorly understood. In particular, it is not known how mutations in a wide range of genes, of apparently unrelated function, give rise to a distinct epilepsy syndrome. This thesis aimed to characterize the neuronal effects of mutations recently identified in KCNC1 (Kv3.1) and Golgi SNARE receptor complex member 2 (GOSR2) that have been shown to cause PME with ataxia. Kv3.1 is a voltage-gated potassium channel important for high frequency neuronal firing. A recurrent p.Arg320His mutation in Kv3.1 had been previously found to be a loss-of-function with a dominant negative effect. I selectively overexpressed Kv3.1R320H in interneurons in vitro and found that it rapidly induced a reduction in dendritic length and neurotoxicity. Repeating these experiments using a lentiviral-based overexpression strategy, I again observed morphological defects as well as alterations in firing. Using an oocyte expression system, we excluded omega currents through the voltage-sensor domain of the channel as a potential mechanism of toxicity. The second mutation studied was a p.G144W loss-of-function mutation in GOSR2, an essential protein required for ER-Golgi transport. In primary cortical cultures, I found that overexpression of GOSR2G144W resulted in a significant reduction of miniature excitatory post-synaptic currents, which was not caused by a reduction in excitatory synapse number. I also characterised the effects of this mutation on dendritic outgrowth in Purkinje cells of the mouse cerebellum. Overall, I suggest that the pathological effects of these two distinct PME mutations converge on dendritic dysfunction, which may generally apply across the PMEs.

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