Progressive neuronal inclusion formation and axonal degeneration in CHMP2B mutant transgenic mice
Abstract
Mutations in the charged multivesicular body protein 2B (CHMP2B) gene cause frontotemporal lobar degeneration. The mutations lead to C-terminal truncation of the CHMP2B protein. We generated Chmp2b knockout mice and transgenic mice expressing either wild-type or C-terminally truncated mutant CHMP2B. The transgenic CHMP2B mutant mice have decreased survival and show progressive neurodegenerative changes including gliosis and increasing accumulation of p62- and ubiquitin-positive inclusions. The inclusions are negative for the TAR DNA binding protein 43 and fused in sarcoma proteins, mimicking the inclusions observed in patients with CHMP2B mutation. Mice transgenic for mutant CHMP2B also develop an early and progressive axonopathy characterized by numerous amyloid precursor protein-positive axonal swellings, implicating altered axonal function in disease pathogenesis. These findings were not observed in Chmp2b knockout mice or in transgenic mice expressing wild-type CHMP2B, indicating that CHMP2B mutations induce degenerative changes through a gain of function mechanism. These data describe the first mouse model of dementia caused by CHMP2B mutation and provide new insights into the mechanisms of CHMP2B-induced neurodegeneration.
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Transgenic mice expressing mutant CHMP2B develop progressive neurological defects, axonal pathology, early mortality, and neuronal loss reminiscent of FTD.
“Transgenic mice expressing mutant CHMP2B develop progressive neurological defects, axonal pathology, early mortality and neuronal loss reminiscent of FTD [270,271].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [271]
Pathogenic CHMP2B mutations act predominantly through gain-of-function toxicity.
“suggesting predominantly gain of function toxicity in association with pathogenic CHMP2B mutations.”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [271]
Few phenotypes were noted in chmp2b knockout animals.
“few phenotypes were noted in chmp2b knockout animals [271]”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [271]
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BackgroundInfluentialThe FReJA consortium, Clayton, E. L., Mizielinska, S., Edgar, J. R., Nielsen, T. T., Marshall, S., Norona, F. E., Robbins, M., Damirji, H., Holm, I. E., et al. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1475-3 · Cited by 96 · see citing works
Self-citation
- Authors
- Ghazi-Noori, S., Froud, K. E., Mizielinska, S., Powell, C., Smidak, M., Fernandez de Marco, M., O’Malley, C., Farmer, M., Parkinson, N., Fisher, E. M. C., Asante, E. A., Brandner, S., Collinge, J., & Isaacs, A. M.
- Affiliations
- MRC Prion Unit (GB)
- UCL Queen Square Institute of Neurology (GB)
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-02-24
- Volume
- 135
- Issue
- 3
- Pages
- 819-832
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- OpenAlex
- W1987253734
- Cited by
- 115
- References
- 63
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 5 · 2023: 11 · 2022: 7 · 2021: 7 · 2020: 9 · 2019: 6 · 2018: 12 · 2017: 10 · 2016: 8 · 2015: 11 · 2014: 5 · 2013: 5 · 2012: 9
- FWCI
- 6.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- CHMP2B, frontotemporal lobar degeneration, axonal degeneration, axonopathy, amyloid precursor protein, p62, ubiquitin, gliosis, gain-of-function mutations, neurodegeneration, mouse model, transgenic mice
- MeSH terms
- Aging, Animals, Axons, Inclusion Bodies, Gliosis, Humans, Immunohistochemistry, Introns, Mice, Transgenic, Microscopy, Electron, Nerve Degeneration, Neurons, RNA, Blotting, Western, Survival Analysis, Mice, Knockout, Mice, Kaplan-Meier Estimate, Endosomal Sorting Complexes Required for Transport, Frontotemporal Dementia, Real-Time Polymerase Chain Reaction
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