Journal
ACTA NEUROPATHOLOGICA
Volume 130, Issue 4, Pages 511-523Publisher
SPRINGER
DOI: 10.1007/s00401-015-1475-3
Keywords
CHMP2B; FTD; ESCRT; Lysosome; Lysosomal storage disorder
Categories
Funding
- UK Medical Research Council
- Noro Nordisk Foundation
- Department of Health's NIHR Biomedical Research Centres funding scheme
- MRC [MC_U123160653, MC_U123192748, MR/J004022/1] Funding Source: UKRI
- Alzheimers Research UK [ARUK-PPG2014B-5] Funding Source: researchfish
- Medical Research Council [MC_U123192748, MC_U123160653, MR/J004022/1] Funding Source: researchfish
- Motor Neurone Disease Association [Isaacs/Apr13/818-791] Funding Source: researchfish
- Novo Nordisk Fonden [NNF11OC1014514] Funding Source: researchfish
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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.
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