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

• DOI: 10.1007/s00401-015-1475-3
• Publication Date: 2015-09-10T18:58:34Z
• Authors: Emma L. Clayton; Sarah Mizielinska; James R. Edgar; Troels Tolstrup N...; Sarah Marshall; Frances E. Norona; Miranda Robbins; Hana Damirji; Ida E. Holm; Peter Johannsen; Jørgen E. Nielsen; Emmanuel A. Asante; John Collinge; Adrian M. Isaacs
• Keywords: Male; 0301 basic medicine; 572; Lysosomal storage disorder; Neurons/metabolism; Clinical Neurology; Mice, Transgenic; Nerve Tissue Proteins; 612; Lysosomes/metabolism; Transgenic; Pathology and Forensic Medicine; ESCRT; Microglia/metabolism; Mice; Frontotemporal Dementia/genetics; Cellular and Molecular Neuroscience; 03 medical and health sciences; 80 and over; Brain/metabolism; Nerve Tissue Proteins/genetics; Animals; Humans; Aged; Aged, 80 and over; Neurons; Original Paper; Endosomal Sorting Complexes Required for Transport/genetics; Endosomal Sorting Complexes Required for Transport; Animal; CHMP2B; Brain; FTD; Middle Aged; Lysosome; 3. Good health; Disease Models, Animal; Frontotemporal Dementia; Disease Models; Mutation; Disease Progression; Female; Microglia; Protein Multimerization; Lysosomes

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 occur 3 months of age increase both size number over time. These not observed expressing wild-type CHMP2B, or non-transgenic controls, indicating they specific caused CHMP2B. Ultrastructural analysis immuno- gold labelling confirmed derived from endolysosomal system. Consistent with these findings, mutation patient brains contain morphologically similar significantly more frequently human brain than neurodegenerative disease age-matched control brains. data suggest is major FTD mutation. Recent evidence suggests two other genes associated FTD, GRN TMEM106B important for function. Our identification now provides dysfunction degenerative pathway FTD.