CHMP2B mutants linked to frontotemporal dementia impair maturation of dendritic spines
Open Access
- 1 September 2010
- journal article
- Published by The Company of Biologists in Journal of Cell Science
- Vol. 123 (17), 2943-2954
- https://doi.org/10.1242/jcs.068817
Abstract
The highly conserved ESCRT-III complex is responsible for deformation and cleavage of membranes during endosomal trafficking and other cellular activities. In humans, dominant mutations in the ESCRT-III subunit CHMP2B cause frontotemporal dementia (FTD). The decade-long process leading to this cortical degeneration is not well understood. One possibility is that, akin to other neurodegenerative diseases, the pathogenic protein affects the integrity of dendritic spines and synapses before any neuronal death. Using confocal microscopy and 3D reconstruction, we examined whether expressing the FTD-linked mutants CHMP2Bintron5 and CHMP2BΔ10 in cultured hippocampal neurons modified the number or structure of spines. Both mutants induced a significant decrease in the proportion of large spines with mushroom morphology, without overt degeneration. Furthermore, CHMP2BΔ10 induced a drop in frequency and amplitude of spontaneous excitatory postsynaptic currents, suggesting that the more potent synapses were lost. These effects seemed unrelated to changes in autophagy. Depletion of endogenous CHMP2B by RNAi resulted in morphological changes similar to those induced by mutant CHMP2B, consistent with dominant-negative activity of pathogenic mutants. Thus, CHMP2B is required for spine growth. Taken together, these results demonstrate that a mutant ESCRT-III subunit linked to a human neurodegenerative disease can disrupt the normal pattern of spine development.Keywords
This publication has 39 references indexed in Scilit:
- Molecular mechanism of multivesicular body biogenesis by ESCRT complexesNature, 2010
- Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutationsHuman Molecular Genetics, 2010
- Amyloid beta from axons and dendrites reduces local spine number and plasticityNature Neuroscience, 2009
- Structural basis for ESCRT-III protein autoinhibitionNature Structural & Molecular Biology, 2009
- Membrane scission by the ESCRT-III complexNature, 2009
- Functional Reconstitution of ESCRT-III Assembly and DisassemblyCell, 2009
- Helical Structures of ESCRT-III Are Disassembled by VPS4Science, 2008
- Plasma membrane deformation by circular arrays of ESCRT-III protein filamentsThe Journal of cell biology, 2008
- Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative diseaseThe Journal of cell biology, 2007
- Release of autoinhibition converts ESCRT-III components into potent inhibitors of HIV-1 buddingProceedings of the National Academy of Sciences of the United States of America, 2006