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Acta Neuropathol. 2015 Oct;130(4):511-23. doi: 10.1007/s00401-015-1475-3. Epub 2015 Sep 10.

Frontotemporal dementia caused by CHMP2B mutation is characterised by neuronal lysosomal storage pathology.

Author information

1
Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
2
Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK.
3
Neurogenetics Research Laboratory, Department of Neurology, Danish Dementia Research Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
4
Laboratory for Experimental Neuropathology, Department of Pathology, Randers Hospital, 8930, Randers NØ, Denmark.
5
Institute of Clinical Medicine, Aarhus University, 8000, Aarhus C, Denmark.
6
Memory Clinic, Department of Neurology, Danish Dementia Research Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
7
Department of Cellular and Molecular Medicine, Section of Neurogenetics, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.
8
MRC Prion Unit, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
9
Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK. a.isaacs@prion.ucl.ac.uk.

Abstract

Mutations in the charged multivesicular body protein 2B (CHMP2B) cause frontotemporal dementia (FTD). We report that mice which express FTD-causative mutant CHMP2B at physiological levels develop a novel lysosomal storage pathology characterised by large neuronal autofluorescent aggregates. The aggregates are an early and progressive pathology that occur at 3 months of age and increase in both size and number over time. These autofluorescent aggregates are not observed in mice expressing wild-type CHMP2B, or in non-transgenic controls, indicating that they are a specific pathology caused by mutant CHMP2B. Ultrastructural analysis and immuno- gold labelling confirmed that they are derived from the endolysosomal system. Consistent with these findings, CHMP2B mutation patient brains contain morphologically similar autofluorescent aggregates. These aggregates occur significantly more frequently in human CHMP2B mutation brain than in neurodegenerative disease or age-matched control brains. These data suggest that lysosomal storage pathology is the major neuronal pathology in FTD caused by CHMP2B mutation. Recent evidence suggests that two other genes associated with FTD, GRN and TMEM106B are important for lysosomal function. Our identification of lysosomal storage pathology in FTD caused by CHMP2B mutation now provides evidence that endolysosomal dysfunction is a major degenerative pathway in FTD.

KEYWORDS:

CHMP2B; ESCRT; FTD; Lysosomal storage disorder; Lysosome

PMID:
26358247
PMCID:
PMC4575387
DOI:
10.1007/s00401-015-1475-3
[Indexed for MEDLINE]
Free PMC Article

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