| Summary: | Mutations in the charged multivesicular body protein 2B gene (CHMP2B) cause frontotemporal dementia termed frontotemporal dementia linked to chromosome 3 (FTD-3) in a large Danish pedigree and also in an unrelated Belgian familial FTD patient. Genetic analyses on the Danish pedigree and the role of CHMP2B mutations in frontotemporal dementia are reported. The clinicopathological spectrum of FTD-3 and other FTD subtypes is also described. CHMP2B is a component of the endosomal sorting complex required for transport (ESCRT-III), which is required for formation and function of the multivesicular body (MVB), an endosomal structure that fuses with the lysosome to degrade endocytosed proteins. Cellular models of CHMP2B mutations showed an enlarged late endosomal phenotype and an abnormal pattern of ubiquitination. Functional studies demonstrated a specific disruption of endosome-lysosome fusion but not sorting of endocytosed receptors by the MVB. Investigations into the mechanism of impaired fusion suggested impaired recruitment of the GTPase Rab7, known to be necessary for vesicular fusion, onto endosomes in CHMP2B mutant cells. Studies of patient tissue revealed a novel endosomal pathology in CHMP2B mutation-positive patient brains and also abnormal endosomes in patient fibroblasts. These data indicate that defects in endosomal fusion events can lead to neurodegeneration and suggest a potential pathogenic mechanism for CHMP2B mutations.
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