eprintid: 10063313 rev_number: 23 eprint_status: archive userid: 608 dir: disk0/10/06/33/13 datestamp: 2018-12-05 09:23:00 lastmod: 2021-10-01 23:57:43 status_changed: 2018-12-05 09:23:00 type: article metadata_visibility: show creators_name: Clayton, EL creators_name: Milioto, C creators_name: Muralidharan, B creators_name: Norona, FE creators_name: Edgar, JR creators_name: Soriano, A creators_name: Jafar-Nejad, P creators_name: Rigo, F creators_name: Collinge, J creators_name: Isaacs, AM title: Frontotemporal dementia causative CHMP2B impairs neuronal endolysosomal traffic-rescue by TMEM106B knockdown ispublished: pub divisions: UCL divisions: B02 divisions: C07 divisions: DF9 divisions: FA5 divisions: D07 divisions: F81 divisions: F86 keywords: frontotemporal dementia, trafficking, ESCRT, CHMP2B, TMEM106B note: © The Author(s) 2018. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. abstract: 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. date: 2018-12 date_type: published official_url: https://doi.org/10.1093/brain/awy284 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green article_type_text: Journal Article verified: verified_manual elements_id: 1605861 doi: 10.1093/brain/awy284 pii: 5212875 lyricists_name: Clayton, Emma lyricists_name: Collinge, John lyricists_name: Isaacs, Adrian lyricists_name: Milioto, Carmelo lyricists_name: Muralidharan, Bhavana lyricists_id: ELCLA56 lyricists_id: JCOLL20 lyricists_id: AISAA22 lyricists_id: CMILI40 lyricists_id: BMURA64 actors_name: Flynn, Bernadette actors_id: BFFLY94 actors_role: owner full_text_status: public publication: Brain volume: 141 number: 12 pagerange: 3428-3442 event_location: England issn: 1460-2156 citation: Clayton, EL; Milioto, C; Muralidharan, B; Norona, FE; Edgar, JR; Soriano, A; Jafar-Nejad, P; ... Isaacs, AM; + view all <#> Clayton, EL; Milioto, C; Muralidharan, B; Norona, FE; Edgar, JR; Soriano, A; Jafar-Nejad, P; Rigo, F; Collinge, J; Isaacs, AM; - view fewer <#> (2018) Frontotemporal dementia causative CHMP2B impairs neuronal endolysosomal traffic-rescue by TMEM106B knockdown. Brain , 141 (12) pp. 3428-3442. 10.1093/brain/awy284 <https://doi.org/10.1093/brain%2Fawy284>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10063313/1/awy284.pdf document_url: https://discovery.ucl.ac.uk/id/eprint/10063313/6/awy284_suppl_data.pdf