The role of CHMP2BIntron5 in autophagy and frontotemporal dementia

Abstract

Charged multivesicular body protein 2B (CHMP2B) - a component of the endosomal complex required for transport-III (ESCRT-III) - is responsible for the vital membrane deformation functions in autophagy and endolysosomal trafficking. A dominant mutation in CHMP2B (CHMP2B^Intron5) is associated with a subset of heritable frontotemporal dementia - frontotemporal dementia linked to chromosome 3 (FTD-3). ESCRT-III recruits Vps4, an AAA-ATPase that abscises the membrane during various cellular processes including autophagy and intraluminal vesicle formation. CHMP2B^Intron5 results in a C-terminus truncation removing an important Vps4 binding site as well as eliminating the normal autoinhibitory resting state of CHMP2B. CHMP2B is expressed in most cell types but seems to be especially vital for proper neuronal function. CHMP2B^Intron5-mediated phenotypes include misregulation of transmembrane receptors, accumulation of multilamellar structures, abnormal lysosomal morphology, down regulation of a brain-specific micro RNA (miRNA-124), abnormal dendritic spine morphology, decrease in dendritic arborization, and cell death. Currently, transgenic-fly,-mouse, and -human cell lines are being used to better understand the diverse phenotypes and develop therapeutic approaches for the CHMP2B^Intron5-induced FTD-3. This article is part of a Special Issue entitled SI:Autophagy.

Keywords: Autophagy; CHMP2B(Intron5); ESCRT-III; Endolysosome; FTD-ALS; Frontotemporal dementia.

Figure 1

Mutations in the CHMP2B gene causing FTD and other neurodegenerative diseases. A. There are several CHMP2B mutations that have been found to cause diseases on the FTD-ALS spectrum (I29V, T104N, D148Y, Q165X, M178V, and Q206H; orange boxes) as well as other neurodegenerative disorders; corticobasal degeneration caused by N143S (purple box). B. Functional wild type CHMP2B domains and altered CHMP2B^Intron5 protein. Wild type CHMP2B is a 213 amino acid protein with two coiled-coil (CC) domains as well as a microtubule interacting and transport interacting motif (MIM). The N-terminus contains basic alpha helices and the C-terminus contains acidic alpha helices, leading to an auto-inhibitory self-binding. CHMP2B^Intron5 loses much of the acidic C-terminus, decreasing its autoinhibition and removing the MIM, which is a Vps4 binding site. E, Exon; PMA, primary muscular atrophy; CBD, corticobasal degeneration; SD, semantic dementia; FTD, frontotemporal dementia; * denotes mutation causing CHMP2B^Intron5 and CHMP2B^Delta10.

Figure 2

CHMP2B^Intron5 causes a diverse array of neuronal pathologies. The known molecular and structural bases of this neurodegeneration include: misregulation of miRNA, accumulation of autophagosomes and MVBs, abnormally sized lysosomes, a decrease in dendritic arborization, an overall increase in dendritic spines but with a decrease in mushroom spines, and misregulation of receptors such as Notch, and EGFR. These pathologies combined not only weaken the cell, but also leads to death of many frontal and temporal neurons.