Frontotemporal dementia causative CHMP2B impairs neuronal endolysosomal traffic-rescue by TMEM106B knockdown.
Clayton, Emma L
Norona, Frances E
Isaacs, Adrian M
Oxford University Press (OUP)
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Clayton, E. L., Milioto, C., Muralidharan, B., Norona, F. E., Edgar, J., Soriano, A., Jafar-Nejad, P., et al. (2018). Frontotemporal dementia causative CHMP2B impairs neuronal endolysosomal traffic-rescue by TMEM106B knockdown.. Brain, 141 (12), 3428-3442. https://doi.org/10.1093/brain/awy284
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.
Brain, Dendrites, Cells, Cultured, Endosomes, Lysosomes, Animals, Mice, Inbred C57BL, Mice, Transgenic, Membrane Proteins, Nerve Tissue Proteins, Neuronal Plasticity, Female, Male, Gene Knockdown Techniques, Endosomal Sorting Complexes Required for Transport, Frontotemporal Dementia
External DOI: https://doi.org/10.1093/brain/awy284
This record's URL: https://www.repository.cam.ac.uk/handle/1810/287263
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/