Ghazi-Noori, S; (2013) Generating and Characterising Knockout and Transgenic Mouse Models of Frontotemporal Dementia Caused by CHMP2B Mutation. Doctoral thesis (PhD), UCL (University College London).

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Abstract

A mutation in the charged multivesicular body protein 2B (CHMP2B) gene, identified in a kindred from the Jutland region of Denmark, segregates with affected family members with clinical presentations of frontotemporal dementia (FTD) and is absent in control populations (Gydesen et al., 1987; Gydesen et al., 2002; Skibinski et al., 2005). The mutation is a G>C transition in the splice acceptor site of exon 6 resulting in two novel splice variants CHMP2BInt5 and CHMP2BA10 leading to C-terminal truncation of the CHMP2B protein (Skibinski et al., 2005). Chmp2b knockout (Chmp2b-/-) mice and transgenic mice expressing either wild-type or C-terminally truncated mutant CHMP2B splice variants CHMP2BInt5 and CHMP2BA10 were generated with the aims of examining the normal function of Chmp2b and the effect of mutant CHMP2B species in vivo, as well as providing insight into a potential common FTD mechanism of disease. Quantification of Chmp2b protein in Chmp2b-/- mice demonstrates a significant (85%) depletion of endogenous Chmp2b in the mouse brain. No pathology is identified in the CNS or muscle tissue of these mice however, they do demonstrate significant motor and behavioural abnormalities. CHMP2BInt5 transgenic mice demonstrate neurodegenerative changes including progressive gliosis, accumulation of CHMP2B, p62 and ubiquitin inclusions which are negative for TDP-43 and FUS proteins, consistent with the inclusion pathology observed in patients with CHMP2B mutation. Furthermore, these mice have reduced survival and develop progressive axonopathy characterized by axonal swellings and accumulation of mitochondria and vesicles likely from the endosome¬lysosome and autophagy pathway, implicating altered axonal function in disease pathogenesis. This thesis describes the first mouse models of FTD-3 caused by CHMP2B mutation and presents evidence consistent with a gain-of-function effect unique to the CHMP2BInt5 isoform and provides new insights into the mechanisms of CHMP2B-induced neurodegeneration.

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