Frontotemporal dementia causative CHMP2B impairs neuronal endolysosomal traffic-rescue by TMEM106B knockdown

Mutations in the endosome-associated protein CHMP2B cause frontotemporal dementia and lead to lysosomal storage pathology in neurons. We here report that physiological levels of mutant CHMP2B causes reduced numbers and significantly impaired trafficking of endolysosomes within neuronal dendrites, accompanied by increased dendritic branching. Mechanistically, this is due to the stable incorporation of mutant CHMP2B onto neuronal endolysosomes, which we show renders them unable to traffic within dendrites. This defect is due to the inability of mutant CHMP2B to recruit the ATPase VPS4, which is required for release of CHMP2B from endosomal membranes. Strikingly, both impaired trafficking and the increased dendritic branching were rescued by treatment with antisense oligonucleotides targeting the well validated frontotemporal dementia risk factor TMEM106B, which encodes an endolysosomal protein. This indicates that reducing TMEM106B levels can restore endosomal health in frontotemporal dementia. As TMEM106B is a risk factor for frontotemporal dementia caused by both C9orf72 and progranulin mutations, and antisense oligonucleotides are showing promise as therapeutics for neurodegenerative diseases, our data suggests a potential new strategy for treating the wide range of frontotemporal dementias associated with endolysosomal dysfunction

Early microgliosis precedes neuronal loss and behavioural impairment in mice with a frontotemporal dementia-causing CHMP2B mutation

Frontotemporal dementia (FTD)-causing mutations in the CHMP2B gene lead to the generation of mutant C-terminally truncated CHMP2B. We report that transgenic mice expressing endogenous levels of mutant CHMP2B developed late-onset brain volume loss associated with frank neuronal loss and FTD-like changes in social behaviour. These data are the first to show neurodegeneration in mice expressing mutant CHMP2B and indicate that our mouse model is able to recapitulate neurodegenerative changes observed in FTD. Neuroinflammation has been increasingly implicated in neurodegeneration, including FTD. Therefore, we investigated neuroinflammation in our CHMP2B mutant mice. We observed very early microglial proliferation that develops into a clear pro-inflammatory phenotype at late stages. Importantly, we also observed a similar inflammatory profile in CHMP2B patient frontal cortex. Aberrant microglial function has also been implicated in FTD caused by GRN, MAPT and C9orf72 mutations. The presence of early microglial changes in our CHMP2B mutant mice indicates neuroinflammation may be a contributing factor to the neurodegeneration observed in FTD

Individual microglia move rapidly and directly to nerve lesions in the leech central nervous system.

Small cells called microglia, which collect at nerve lesions, were tracked as they moved within the leech nerve cord to crushes made minutes or hours before. The aim of this study was to determine whether microglia respond as a group and move en masse or instead move individually, at different rates, and whether they move along axons directly to the lesion or take another route, such as along the edges of the nerve cord. Cell nuclei in living nerve cords were stained with Hoechst 33258 dye and observed under dim ultraviolet illumination using fluorescence optics, a low-light video camera, and computer-assisted signal enhancement. Muscular movements of the cord were selectively reduced by bathing in 23 mM MgCl2. Regions of nerve cord within 300 microns of the crush were observed for 2-6 hr. Only a fraction of microglia, typically less than 50%, moved at any time, traveling toward the lesion at speeds up to 7 microns/min. Cells were moving as soon as observation began, within 15 min of crushing, and traveled directly toward the lesion along axons or axon tracts. Movements and roles of leech microglia are compared with their vertebrate counterparts, which are also active and respond to nerve injury