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 (CHMP2BIntron5) 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. CHMP2BIntron5 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. CHMP2BIntron5-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 CHMP2BIntron5-induced FTD-3.

Oligodendroglial deletion of ESCRT‐I component TSG101 causes spongiform encephalopathy

“…The brains of FTD-3 patients with mutations in CHMP2B show many similar changes, including demyelination, gliosis and accumulation of ubiquitinated inclusions and p62, suggesting that loss of ESCRT-I function has similar effects to loss of ESCRT-III. It has been suggested that mutations in CHMP2B cause FTD-3 because they disrupt late endosome-lysosome fusion and autophagy (Lee and Gao, 2009;Urwin et al, 2010;Clayton et al, 2015;Krasniak and Ahmad, 2016), but our study shows that loss of RAB7, which mediates late endosome-to-lysosome trafficking and autophagosome-lysosome fusion events, does not cause vacuolation.…”

Expression of mutant CHMP2B linked to neurodegeneration in humans disrupts circadian rhythms inDrosophila

“…The endosomal‐lysosmal pathway delivers transmembrane proteins to the lysosomal lumen for degradation . CHMP2B, a subunit of Endosomal Sorting Complex Required for Transport‐III (ESCRT‐III), mediates the endosomal sorting of ubiquitinated transmembrane proteins into the multivesicular bodies (MVBs) for transport to lysosomes . Consequently, CHMP2B and other ESCRT subunits play a critical role in the regulation of multiple cell surface receptors and their signaling cascades .…”

Oocytes, embryos and pluripotent stem cells from a biomedical perspective

“…The Danish version of FTD3 has spread in a large family and is caused by a single nucleotide mutation translated into shortened and altered C-terminus of the CHMP2B protein (Skibinski et al, 2005;Urwin et al, 2010;Zhang et al, 2017). CHMP2B is an important part of the endosomal sorting complex required for transport-III (ESCRT-III) and for a proper function of the intracellular endolysosomal pathway (Krasniak and Ahmad, 2016;Urwin et al, 2010;van der Zee et al, 2008). The mutation results in truncated CHMP2B unable to mediate the endosomal-lysosomal fusion and processing.…”