Abstract
Frontotemporal dementia (FTD)-causing mutations in the CHMP2B gene lead to the generation of mutant C-terminally truncated CHMP2B. We report that transgenic mice expressing endogenous levels of mutant CHMP2B developed late-onset brain volume loss associated with frank neuronal loss and FTD-like changes in social behaviour. These data are the first to show neurodegeneration in mice expressing mutant CHMP2B and indicate that our mouse model is able to recapitulate neurodegenerative changes observed in FTD. Neuroinflammation has been increasingly implicated in neurodegeneration, including FTD. Therefore, we investigated neuroinflammation in our CHMP2B mutant mice. We observed very early microglial proliferation that develops into a clear pro-inflammatory phenotype at late stages. Importantly, we also observed a similar inflammatory profile in CHMP2B patient frontal cortex. Aberrant microglial function has also been implicated in FTD caused by GRN, MAPT and C9orf72 mutations. The presence of early microglial changes in our CHMP2B mutant mice indicates neuroinflammation may be a contributing factor to the neurodegeneration observed in FTD.
Highlights
Frontotemporal dementia (FTD) is a common cause of youngonset dementia
We applied a tensor-based morphometry map that does not require manual delineation of regions of interest or isolation of specific structures [26]. This automated analysis revealed significant bilateral volume loss in the thalamus and cortex of CHMP2BIntron5 mice compared with both non-transgenic (Fig. 1A) and CHMP2BWildtype controls (Supplementary Material, Fig. S1) and no significant difference between CHMP2BWildtype and nontransgenic mice
We have shown previously that these particular brain regions harbour inclusion pathology [15,25], and these findings are consistent with brain volume changes observed by Magnetic resonance imaging (MRI) in charged multivesicular body protein 2B (CHMP2B)-FTD patients [6,27,28], suggesting that brain atrophy is occurring in CHMP2BIntron5 mice
Summary
Frontotemporal dementia (FTD) is a common cause of youngonset dementia. FTD shares a clinical spectrum with amyotrophic lateral sclerosis (ALS), with both diseases sharing common pathologies and genetic causes [2]. Familial FTD can be caused by mutations in a number of diverse genes. The most common causes of FTD are mutations in the genes that encode C9orf, tau (MAPT) and progranulin (GRN), with less common causes identified as mutations in valosin-containing protein, TDP-43 (TARDBP), fused in sarcoma and charged multivesicular body protein 2B (CHMP2B) [3]. The location of the mutation in a splice acceptor site results in the production of two variants of C-terminally truncated CHMP2B proteins: CHMP2BIntron in which the final 36 amino acids are replaced with a single valine residue, or CHMP2BD10 in which the final 36 amino acids are replaced with 29 nonsense residues [5]. Further evidence that C-terminal truncation of CHMP2B leads to FTD was found in a subsequent study in a Belgian FTD cohort, where a distinct truncation mutation CHMP2BQ165X that leads to the loss of the final 49 amino acids was discovered [6,7]
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